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. 2018 Nov 8;11(11):CD012853.
doi: 10.1002/14651858.CD012853.pub2.

Cannabis for the treatment of Crohn's disease

Tahir S Kafil  1 , Tran M Nguyen, John K MacDonald, Nilesh Chande
Affiliations

Cannabis for the treatment of Crohn's disease

Tahir S Kafil et al. Cochrane Database Syst Rev. .

Abstract

Background: 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. The endocannabinoid system provides a potential therapeutic target for cannabis and cannabinoids and animal models have shown benefit in decreasing inflammation. However, there is also evidence to suggest transient adverse events such as weakness, dizziness and diarrhea, and an increased risk of surgery in people with CD who use cannabis.

Objectives: The objectives were to assess the efficacy and safety of cannabis and cannabinoids for induction and maintenance of remission in people with CD.

Search methods: We searched MEDLINE, Embase, AMED, PsychINFO, the Cochrane IBD Group Specialized Register, CENTRAL, ClinicalTrials.Gov, and the European Clinical Trials Register up to 17 October 2018. We searched conference abstracts, references and we also contacted researchers in this field for upcoming publications.

Selection criteria: Randomized controlled trials comparing any form of cannabis or its cannabinoid derivatives (natural or synthetic) to placebo or an active therapy for adults with Crohn's disease were included.

Data collection and analysis: Two authors independently screened search results, extracted data and assessed bias using the Cochrane risk of bias tool. The primary outcomes were clinical remission and relapse. Remission is commonly defined as a Crohn's disease activity index (CDAI) of < 150. Relapse is defined as a CDAI > 150. Secondary outcomes included clinical response, endoscopic remission, endoscopic improvement, histological improvement, quality of life, C-reactive protein (CRP) and fecal calprotectin measurements, adverse events (AEs), serious AEs, withdrawal due to AEs, and cannabis dependence and withdrawal effects. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. For continuous outcomes, we calculated the mean difference (MD) and 95% CI. Data were combined for analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). Data were analyzed on an intention-to-treat basis and the overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria.

Main results: Three studies (93 participants) that assessed cannabis in people with active CD met the inclusion criteria. One ongoing study was also identified. Participants in two of the studies were adults with active Crohn's disease who had failed at least one medical treatment. The inclusion criteria for the third study were unclear. No studies that assessed cannabis therapy in quiescent CD were identified. The studies were not pooled due to differences in the interventional drug.One small study (N = 21) compared eight weeks of treatment with cannabis cigarettes containing 115 mg of D9-tetrahydrocannabinol (THC) to placebo cigarettes containing cannabis with the THC removed in participants with active CD. This study was rated as high risk of bias for blinding and other bias (cannabis participants were older than placebo). The effects of cannabis on clinical remission were unclear. Forty-five per cent (5/11) of the cannabis group achieved clinical remission compared with 10% (1/10) of the placebo group (RR 4.55, 95% CI 0.63 to 32.56; very low certainty evidence). A difference was observed in clinical response (decrease in CDAI score of >100 points) rates. Ninety-one per cent (10/11) of the cannabis group achieved a clinical response compared to 40% (4/10) of the placebo group (RR 2.27, 95% CI 1.04 to 4.97; very low certainty evidence). More AEs were observed in the cannabis cigarette group compared to placebo (RR 4.09, 95% CI 1.15 to 14.57; very low certainty evidence). These AEs were considered to be mild in nature and included sleepiness, nausea, difficulty with concentration, memory loss, confusion and dizziness. This study did not report on serious AEs or withdrawal due to AEs.One small study (N = 22) compared cannabis oil (5% cannabidiol) to placebo oil in people with active CD. This study was rated as high risk of bias for other bias (cannabis participants were more likely than placebo participants to be smokers). There was no difference in clinical remission rates. Forty per cent (4/10) of cannabis oil participants achieved remission at 8 weeks compared to 33% (3/9) of the placebo participants (RR 1.20, 95% CI 0.36 to 3.97; very low certainty evidence). There was no difference in the proportion of participants who had a serious adverse event. Ten per cent (1/10) of participants in the cannabis oil group had a serious adverse event compared to 11% (1/9) of placebo participants (RR 0.90, 95% CI 0.07 to 12.38, very low certainty evidence). Both serious AEs were worsening Crohn's disease that required rescue intervention. This study did not report on clinical response, CRP, quality of life or withdrawal due to AEs.One small study (N= 50) compared cannabis oil (15% cannabidiol and 4% THC) to placebo in participants with active CD. This study was rated as low risk of bias. Differences in CDAI and quality of life scores measured by the SF-36 instrument were observed. The mean quality of life score after 8 weeks of treatment was 96.3 in the cannabis oil group compared to 79.9 in the placebo group (MD 16.40, 95% CI 5.72 to 27.08, low certainty evidence). After 8 weeks of treatment, the mean CDAI score was118.6 in the cannabis oil group compared to 212.6 in the placebo group (MD -94.00, 95%CI -148.86 to -39.14, low certainty evidence). This study did not report on clinical remission, clinical response, CRP or AEs.

Authors' 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.

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Conflict of interest statement

Tahir S Kafil: None known

Tran M Nguyen: None known

John K MacDonald: None known

Nilesh Chande has received funds from AbbVie, Ferring, and Takdeda for consulting; and payment for lectures from Abbvie and Actavis. All of these financial activities are outside the submitted work.

Figures

1
1
Flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Cannabis cigarettes (115 mg THC) versus placebo cigarettes, Outcome 1 Clinical remission at 8 weeks.
1.2
1.2. Analysis
Comparison 1 Cannabis cigarettes (115 mg THC) versus placebo cigarettes, Outcome 2 Clinical response at 8 weeks.
1.3
1.3. Analysis
Comparison 1 Cannabis cigarettes (115 mg THC) versus placebo cigarettes, Outcome 3 Adverse events.
1.4
1.4. Analysis
Comparison 1 Cannabis cigarettes (115 mg THC) versus placebo cigarettes, Outcome 4 Decrease in CRP of more than 0.5 mg/dL from week 0 to week 8.
2.1
2.1. Analysis
Comparison 2 Cannabis oil (5% cannabidiol sublingual oil) versus placebo oil, Outcome 1 Clinical remission at 8 weeks.
2.2
2.2. Analysis
Comparison 2 Cannabis oil (5% cannabidiol sublingual oil) versus placebo oil, Outcome 2 Serious adverse events.
3.1
3.1. Analysis
Comparison 3 Cannabis oil (15% cannabidiol and 4% THC) versus placebo oil, Outcome 1 Quality of life at 8 weeks.
3.2
3.2. Analysis
Comparison 3 Cannabis oil (15% cannabidiol and 4% THC) versus placebo oil, Outcome 2 CDAI at 8 weeks.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD012853

References

References to studies included in this review

Naftali 2013a {published and unpublished data}
    1. Naftali T, Bar‐Lev L, Gabay G, Chowers Y, Dotan I, Bronshtein M, et al. Tetrahydrocannabinol (THC) rich medical cannabis induces clinical and biochemical improvement with a steroid sparing effect in active Crohn's disease. Gastroenterology 2012;1:S780.
    1. 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. Clinical Gastroenterology and Hepatology 2013;11(10):1276‐80. - PubMed
Naftali 2017a {published and unpublished data}
    1. Naftali T, Mechoulam R, Gabay G, Stein A, Bronshtein M, Mari A, et al. Cannabidiol treatment does not effect active Crohn's disease. Gastroenterology 2013;1:S180.
    1. Naftali T, Mechulam R, Marii A, Gabay G, Stein A, Bronshtain M, et al. Low‐dose cannabidiol is safe but not effective in the treatment for Crohn’s Disease, a randomized controlled trial. Digestive Diseases and Sciences 2017;62:1615–20. - PubMed
Naftali 2017b {published and unpublished data}
    1. Naftali T, Schlieder LBL, Konikoff FM. The effect of cannabis on Crohn's Disease patients. International Association of Cannabis Medicine (IACM). 2017.

References to studies excluded from this review

Naftali 2013b {published and unpublished data}
    1. Naftali T, Barlev L, Gabay G, Chowers Y, Dotan I, Stein A, et al. Tetrahydrocannabinol (THC) induces clinical and biochemical improvement with a steroid sparing effect in active inflammatory bowel disease. Journal of Crohn's and Colitis 2013;7(Supplement1):S153.

References to ongoing studies

NCT03467620 {published data only}
    1. NCT03467620. Cannabidiol Usage as an Adjunct Therapy for Crohn's Disease [Oral Cannabidiol Capsule Usage as an Adjunct Therapy for Crohn's Disease: a Randomized, Placebo‐controlled Study]. clinicaltrials.gov/ct2/show/NCT03467620 (accessed 17 October 2018).

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