Crohn's and ulcerative colitis

Evidence-based guidelines

Guidance on the suggested use of medical cannabis for Crohn's and ulcerative colitis

This evidence-based guidance was reviewed and approved on 1/9/24.

There is insufficient evidence to support or refute that short-term (8-10 week) cannabis treatment reduces inflammation or induces clinical or endoscopic response/remission in patients with active Crohn’s disease or ulcerative colitis (trials for Crohn’s disease: THC-predominant cannabis cigarettes or CBD-rich cannabis oil; trials for ulcerative colitis: CBD-predominant cannabis oral capsule or THC-predominant cannabis cigarettes).

There is limited evidence to support the conclusion that short-term (8-10 week) cannabis treatment may improve patient-reported quality of life in patients with active Crohn’s disease or ulcerative colitis (trials for Crohn’s disease: CBD-rich cannabis oil; trials for ulcerative colitis: CBD-predominant cannabis oral capsule or THC-predominant cannabis cigarettes).

*Developed using level of evidence categories from the 2017 National Academies of Sciences, Engineering, and Medicine report on cannabis (National Academies of Sciences, Engineering, and Medicine, 2017d).

The sections below on Crohn's disease and ulcerative colitis are adapted from published systematic reviews, or randomized controlled trials identified from the Cochrane organization database, or systematic searches of the Ovid-Medline and Embase databases. All trials included patients with active Crohn's disease or ulcerative colitis. Randomized controlled trials (RCT) evidence is primarily among people with mild-moderate Inflammatory Bowel Disease (IBD) severity. Most RCTs used cannabis-based treatments as an adjunctive therapy to standard IBD treatment. Many of the trials required that patients had an insufficient response to 1 or more standard IBD treatments. 

Crohn's disease

Crohn's disease (CD) is a chronic immune-mediated condition of transmural inflammation in the gastrointestinal tract, associated with significant morbidity and decreased quality of life (QoL). The endocannabinoid system provides a potential therapeutic target for cannabis, cannabinoids, and animal models have shown benefits in decreasing inflammation. However, there is also evidence to suggest transient adverse events (AEs) such as weakness, dizziness, diarrhea, and an increased risk of surgery in people with CD who use cannabis. 

In the context of 7 trials, differences in the QoL were reported in 5 of them. The QoL was measured using the general QoL scale, the SF-36 scale, or an unknown scale (Naftali, Bar-Lev Schleider, Dotan, et al., 2013; Naftali, et al., 2017; Naftali, et al., 2018; Naftali, Bar-Lev Schleider, Almog, et al., 2021; Tartakover, et al., 2021). The findings of one trial measuring QoL were not reported (Naftali, et al., 2017). All trials that reported QoL results documented a significant improvement in QoL from baseline to 8 weeks in the cannabis arm compared to the placebo arm ((Naftali, Bar-Lev Schleider, Dotan, et al., 2013; Naftali, et al., 2017; Naftali, Bar-Lev Schleider, Almog, et al., 2021; Tartakover, et al., 2021). Similarly, the cannabis arm reported a higher QoL score at 8 weeks (Naftali, et al., 2018). Out of the five trials that observed an improvement in QoL, four utilized CBD-rich cannabis, while THC-rich cannabis was used in only one trial (Naftali, Bar-Lev Schleider, Dotan, et al., 2013; Naftali, et al., 2017; Naftali, et al., 2018; Naftali, Bar-Lev Schleider, Almog, et al., 2021; Tartakover, et al., 2021). 

When looking at the research on the effects of cannabis and cannabinoids on Crohn-related pain, we find that the evidence is limited. Significantly greater improvements in median pain scores were reported in one study when patients consumed THC-rich cannabis vs the placebo (Naftali, Bar-Lev Schleider, Dotan, et al., 2013). Bowel movement frequency was found to decrease in 2 studies that also utilized THC-rich cannabis, with no differences reported between the control and study groups (Naftali, Bar-Lev Schleider, Almog, et al., 2021; Tartakover, et al., 2021). 

A review of 7 clinical trials conducted by Naftali et al. assessed changes in overall CD activity using the Crohn’s Disease Activity Index (CDAI) (Merck & Co, Inc, 2023; Regueiro & Al Hashash, 2023). The reports from all seven trials indicate a 71% improvement per the CDAI over 16 weeks in participants that received cannabis when compared to placebo groups (Kafil, et al., 2018a; Naftali, Bar-Lev Schleider, Dotan, et al., 2013; Naftali, Barlev, Gabay, et al., 2013; Naftali, et al., 2017; Naftali, et al., 2018; Naftali, Bar-Lev Schleider, Almog, et al., 2021). The 2 trials that did not support the improvement of the CDAI scores numerically improved from baseline to 8 weeks in both the cannabis and placebo arms, with differences from baseline non-significantly favoring cannabis (Naftali, et al., 2017; Tartakover, et al., 2021). 

Symptom improvement included clinical remission as reported by 4 trials and indicated favorable support for treating with cannabis (Naftali, Bar-Lev Schleider, Dotan, et al., 2013; Naftali, et al., 2017). However, of the 4 trials, only 1 demonstrated statistical significance (Naftali, et al., 2018). One trial reported that there were no differences in the levels of inflammatory markers, C-reactive protein, or calprotectin between the trial groups (Naftali, et al., 2017). 

The studies that included trials of THC-rich cigarettes reported no serious AEs (Naftali, Bar-Lev Schleider, Dotan, et al., 2013; Naftali, Barlev, Gabay, et al., 2013). Nausea, sleepiness, concentration, memory loss, confusion, and dizziness were reported by the cannabis arm and were rated as mild severity. The same findings were found in the placebo group (Naftali, Bar-Lev Schleider, Dotan, et al., 2013). However, 5 trials studying the effects of CBD-rich oils found that headache, sleepiness, nausea, and dizziness occurred at similar rates as the placebo group (Naftali, et al., 2017). 

Cochrane meta-analysis was published in Issue 6, 2019. The primary outcomes were clinical remission and relapse. Secondary outcomes included endoscopic response, QOL, AEs, and cannabis dependence and withdrawal effects. 

Three studies met the inclusion criteria. Participants in 2 of the studies were adults with active Crohn's disease who had failed at least 1 medical treatment. One small study compared 8 weeks of treatment with cannabis cigarettes containing 115 mg of delta-9-tetrahydrocannabinol (THC) to placebo cigarettes containing cannabis with the THC removed in participants with active CD. The effects of cannabis on clinical remission were unclear. A difference was observed in clinical response rates. 91% of the cannabis group achieved a clinical response compared to 40% of the placebo group. More AEs were observed in the cannabis cigarette group compared to the placebo group. These AEs were considered mild in nature and included sleepiness, nausea, difficulty with concentration, memory loss, confusion, and dizziness. One small study compared cannabis oil (5% cannabidiol) to placebo oil in people with active CD. There was no difference in clinical remission rates. 40% of cannabis oil participants achieved remission at 8 weeks compared to 33% of the placebo participants. There was no difference in the proportion of participants who had a serious AE. One small study compared cannabis oil (15% cannabidiol and 4% THC) to placebo in participants with active CD. Differences in QoL scores were observed. The mean QoL score after 8 weeks of treatment was 96.3 in the cannabis oil group compared to 79.9 in the placebo group. This study did not report on clinical remission, clinical response, C-reactive protein (CRP), or AEs. 

Conclusions: The effects of cannabis and cannabis oil on Crohn's disease are uncertain. Thus, no firm conclusions regarding the efficacy and safety of cannabis and cannabis oil in adults with active Crohn's disease can be drawn. The effects of cannabis or cannabis oil in quiescent Crohn's disease have not been investigated. Further studies with larger numbers of participants are required to assess the potential benefits and harms of cannabis in Crohn's disease. Future studies should assess the effects of cannabis in people with active and quiescent Crohn's disease. Different doses of cannabis and delivery modalities should be investigated.

Ulcerative colitis

Cannabis and cannabinoids are often promoted as treatments for many illnesses and are widely used among patients with ulcerative colitis (UC). Few studies have evaluated the use of these agents. Further, cannabis has potential for AEs, and the long-term consequences of cannabis and cannabinoid use in UC are unknown. 

A review of 3 trials that measured QoL in UC patients indicated that there was significant improvement in the reported QoL for participants who consumed cannabinoids for a period of 8-10 weeks when compared to those participants on placebo (Irving, et al., 2018; Naftali, Bar-Lev, Schleider, Scklerovsky Benjaminov, et al., 2021; Tartakover, et al., 2021). Additionally, reported outcomes were significant for improving pain related to irritable bowel disease and had a lower risk of AEs when compared to the placebo group (Irving, et al., 2018). Other measures, such as frequency of bowel movements, did not have any statistical significance in either the study or control groups, while another study reports a decline in frequency (Naftali, Bar-Lev, Schleider, Scklerovsky Benjaminov, et al., 2021). 

AEs that were reported for patients who received CBD were ranked as mild to moderate; however, 10% of these patients reported severe neurological events, including disturbed attention, dizziness, and dizziness with joint swelling/muscle twitching. The placebo group had 3 treatment-emergent severe AEs, including 1 event of chest pain (Irving, et al., 2018). 

The most common treatment-related AEs were nervous system disorders (CBD 83% vs 26% PBO), gastrointestinal disorders (CBD 38% vs PBO 16%), and psychiatric disorders (CBD 24% vs PBO 3%); dizziness, somnolence, disturbed attention, and nausea were the most frequent CBD-associated AEs. Infections/infestations were numerically more frequent with CBD (31%) than PBO (10%), with 3 patients receiving CBD versus none on PBO reporting a lower respiratory infection, but the authors did not consider these events to be treatment-related. Tolerability was poor in the CBD arm, 45% (n=13) of patients stopped treatment due to AEs versus 23% (n=7) in the PBO arm; in the CBD arm, dizziness was the AE most likely to cause discontinuation, whereas worsened UC caused discontinuation in the PBO arm (Irving, et al., 2018). Among the 3 trials of smoked THC-predominant cannabis, details of AEs were reported by only 1 trial. Of 32 total patients, AEs that were primarily of mild severity were as follows (% cannabis vs % PBO): cough (41% vs 20%), dizziness (35% vs 6%), confusion (29% vs 6%), difficulty stopping use (29% vs 12%), behavioral change (23% vs 0%), restlessness (11% vs 0%), shortness of breath (6% vs 0%), decreased memory (0% vs 40%). No hallucinations occurred, and no AE resulted in treatment discontinuation (Naftali, Bar-Lev, Schleider, Scklerovsky Benjaminov, et al., 2021). Another small trial using THC-predominant cannabis reported no serious AEs (Kafil, et al., 2018b). 

A Cochrane meta-analysis was published in Issue 6, 2019. The primary outcomes were clinical remission and relapse. Secondary outcomes included endoscopic response, QoL, AEs, and cannabis dependence and withdrawal effects. 

Two studies met the inclusion criteria. One study compared 10 weeks of cannabidiol capsules containing up to 4.7% delta-9-tetrahydrocannabinol (THC) with placebo capsules in participants with mild to moderate UC. The starting dose of cannabidiol was 50 mg twice daily, increasing to 250 mg twice daily if tolerated. Another study compared 8 weeks of therapy with 2 cannabis cigarettes per day containing 0.5 g of cannabis, corresponding to 23 mg THC/day, to placebo cigarettes in participants with UC who did not respond to conventional medical treatment. The effect of cannabidiol capsules (100 mg to 500 mg daily) compared to placebo on clinical remission and response is uncertain. Clinical remission at 10 weeks was achieved by 24% of the cannabidiol group compared to 26% in the placebo group. Clinical response and Serum CRP levels were similar in both groups after 10 weeks of therapy. There may be a clinically meaningful improvement in QoL at 10 weeks. AEs were more frequent in cannabidiol participants compared to placebo. 100% of cannabidiol participants had an AE, compared to 77% of placebo participants. However, these AEs were considered to be mild or moderate in severity. Common AEs included dizziness, disturbance in attention, headache, nausea, and fatigue. More participants in the cannabidiol group withdrew due to an AE than placebo participants. Withdrawals in the cannabidiol group were mostly due to dizziness. Withdrawals in the placebo group were due to worsening UC. The effect of cannabis cigarettes (23 mg THC/day) compared to placebo on mean disease activity, CRP levels, and mean fecal calprotectin levels is uncertain. After 8 weeks, the mean disease activity index score in cannabis participants was 4 compared with 8 in placebo participants. After 8 weeks, the mean change in CRP levels was similar in both groups. No serious AEs were observed. This study did not report on clinical remission, clinical response, QoL, AEs, or withdrawal due to AEs. 

Conclusions: The effects of cannabis and cannabidiol on UC are uncertain. Thus, no firm conclusions regarding the efficacy and safety of cannabis or cannabidiol in adults with active UC can be drawn. There is no evidence for cannabis or cannabinoid use for maintenance of remission in UC. Further studies with a larger number of patients are required to assess the effects of cannabis in UC patients with active and quiescent disease. Different doses of cannabis and routes of administration should be investigated. Lastly, follow-up is needed to assess the long-term safety outcomes of frequent cannabis use. 

References

  1. Irving, P. M., Iqbal, T., Nwokolo, C., Subramanian, S., Bloom, S., Prasad, N., Hart, A., Murray, C., Lindsay, J. O., Taylor, A., Barron, R., & Wright, S. (2018). A randomized, double-blind, placebo-controlled, parallel-group, pilot study of Cannabidiol-rich botanical extract in the symptomatic treatment of ulcerative colitis. Inflammatory Bowel Diseases, 24(4), 714–724. https://doi.org/10.1093/ibd/izy002 
  2. Kafil, T. S., Nguyen, T. M., MacDonald, J. K., & Chande, N. (2018a). Cannabis for the treatment of Crohn’s disease. Cochrane Database of Systematic Reviews, (11). https://doi.org/10.1002/14651858.CD012853.pub2 
  3. Kafil, T. S., Nguyen, T. M., MacDonald, J. K., & Chande, N. (2018b). Cannabis for the treatment of ulcerative colitis. Cochrane Database of Systematic Reviews, (11). https://doi.org/10.1002/14651858.cd012954 
  4. Merck & Co, Inc. Calculators: Crohn disease activity index (CDAI). Merck Manuals Professional Edition. Retrieved August 20, 2023 from https://www.merckmanuals.com/professional/multimedia/clinical-calculator/crohn disease-activity-index-cdai 
  5. Naftali, T., Bar-Lev Schleider, L., Dotan, I., Lansky, E. P., Sklerovsky Benjaminov, F., & Konikoff, F. M. (2013). Cannabis induces a clinical response in patients with crohn’s disease: A prospective placebo-controlled study. Clinical Gastroenterology and Hepatology, 11(10), 1276–1280. https://doi.org/10.1016/j.cgh.2013.04.034 
  6. Naftali, T., Barlev, L., Gabay, G., Chowers, Y., Dotan, I., Stein, A., Bronstein, M., & Konikoff, F. M. (2013). Tetrahydrocannabinol (THC) induces clinical and biochemical improvement with a steroid sparing effect in active inflammatory bowel disease. Journal of Crohn’s and Colitis, 7(Supplement 1), S153. https://doi.org/10.1016/s1873-9946(13)60379-7 
  7. Naftali, T., Mechulam, R., Marii, A., Gabay, G., Stein, A., Bronshtain, M., Laish, I., Benjaminov, F., & Konikoff, F. M. (2017). Low-dose cannabidiol is safe but not effective in the treatment for crohn’s disease, a randomized controlled trial. Digestive Diseases and Sciences, 62(6), 1615–1620. https://doi.org/10.1007/s10620-017-4540-z 
  8. Naftali, T., Bar-Lev Schlieder, L., Konikoff, F., Benjaminov, F., Lish, I., Sergeev, I., & Ringel, Y. (2018). 26th United European Gastroenterology Week Vienna, 2018. United European Gastroenterology Journal, 6(S8), A75.  https://doi.org/10.1177/2050640618792817 
  9. Naftali, T., Bar-Lev Schleider, L., Almog, S., Meiri, D., & Konikoff, F. M. (2021). Oral CBD-rich cannabis induces clinical but not endoscopic response in patients with crohn’s disease, a randomised controlled trial. Journal of Crohn’s and Colitis, 15(11), 1799–1806. https://doi.org/10.1093/ecco-jcc/jjab069
  10. Naftali, T., Bar-Lev Schleider, L., Scklerovsky Benjaminov, F., Konikoff, F. M., Matalon, S. T., & Ringel, Y. (2021). Cannabis is associated with clinical but not endoscopic remission in ulcerative colitis: A randomized controlled trial. PLOS ONE, 16(2). https://doi.org/10.1371/journal.pone.0246871 
  11. National Academies of Science, Engineering, and Medicine (2017). The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. The National Academies Press. https://doi.org/10.17226/24625 
  12. Regueiro, M., & Al Hashash, J. (2023). Overview of the medical management of mild (low risk) Crohn disease in adults. UptoDate. https://www.uptodate.com/contents/overview-of-the-medical-management-of-mild-low-risk-crohn-disease-in-adults
  13. Tartakover Matalon, S., Azar, S., Meiri, D., Hadar, R., Nemirovski, A., Abu Jabal, N., Konikoff, F. M., Drucker, L., Tam, J., & Naftali, T. (2021). Endocannabinoid levels in ulcerative colitis patients correlate with clinical parameters and are affected by cannabis consumption. Frontiers in Endocrinology, 12. https://doi.org/10.3389/fendo.2021.685289