Cannabis and cannabis oil for the treatment of ulcerative colitis

What is ulcerative colitis?

Ulcerative colitis is a chronic, long-term illness that causes inflammation of the colon and rectum. Symptoms may include diarrhea, rectal bleeding, passage of mucus, and abdominal pain. It is characterized by periods of acute flares when people experience symptoms as well as periods of remission when symptoms stop.

What are cannabis and cannabinoids?

Cannabis is a widely used recreational drug that has multiple effects on the body via the endocannabinoid system. Cannabis contains multiple sub-ingredients called cannabinoids. Cannabis and cannabis oil containing specific cannabinoids can cause cognitive changes such as feelings of euphoria and altered sensory perception. However, some cannabinoids, such as cannabidiol, do not have a psychoactive effect. Cannabis and some cannabinoids have been shown to decrease inflammation in animal and laboratory models which suggests it may help people with ulcerative colitis. For example, cannabidiol is one such cannabinoid that has shown anti-inflammatory activity in mice.

What did the researchers investigate?

The researchers evaluated whether cannabis or cannabis oil (cannabidiol) was better than placebo (e.g. fake drug) for treating adults with active ulcerative colitis or ulcerative colitis that is in remission. The researchers searched the medical literature extensively up to 2 January 2018.

What did the researchers find?

Two studies including 92 adult participants with ulcerative colitis were included. Both studies assessed cannabis therapy in participants who had active ulcerative colitis. No studies that assessed cannabis therapy in participants with ulcerative colitis in remission were identified. One study (60 participants) compared 10 weeks of treatment with capsules containing cannabis oil with up to 4.7% D9-tetrahydrocannabinol (THC) to placebo in participants with mild to moderately active ulcerative colitis. The starting dose of cannabidiol was 50 mg twice daily which was increased, if tolerated, to a target of 250 mg twice daily. The other study (32 participants) compared 8 weeks of treatment with two cannabis cigarettes per day containing 0.5 g of cannabis, corresponding to 11.5 mg THC to placebo cigarettes in participants with ulcerative colitis who did not respond to conventional medical treatment.

The study comparing cannabis oil capsules to placebo found no difference in remission rates at 10 weeks. Twenty four (7/29) percent of cannabidiol participants achieved clinical remission compared to 26% (8/31) of placebo participants. The study also showed higher self reported quality of life scores in cannabis oil participants compared to placebo participants. More side-effects were observed in the cannabis oil participants compared to the placebo participants. These side effects were considered to be mild or moderate in severity. Common reported side effects include dizziness, disturbance in attention, headache, nausea and fatigue. No patients in the cannabis oil group had any serious side effects. Ten per cent (3/31) of the placebo group had a serious side effect. Serious side effects in the placebo group included worsening ulcerative colitis and one complicated pregnancy.

The second study comparing two cannabis cigarettes (23 mg THC/day) to placebo cigarettes showed lower disease activity index scores in the cannabis group compared to the placebo group. C-reactive protein and fecal calprotectin levels (both measures of inflammation in the body) were similar in both groups. No serious side effects were reported. This study did not report on remission rates.

Conclusions

The effects of cannabis and cannabis oil on ulcerative colitis are uncertain, thus no firm conclusions regarding the effectiveness and safety of cannabis or cannabis oil in adults with active ulcerative colitis can be drawn. There is no evidence for cannabis or cannabis oil use for maintenance of remission in ulcerative colitis. Further studies with a larger number of participants are required to assess the effects of cannabis in people with active and inactive ulcerative colitis. 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.

Authors' 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.

Read the full abstract...
Background: 

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

Objectives: 

To assess the efficacy and safety of cannabis and cannabinoids for the treatment of patients with UC.

Search strategy: 

We searched MEDLINE, Embase, WHO ICTRP, AMED, PsychINFO, the Cochrane IBD Group Specialized Register, CENTRAL, ClinicalTrials.Gov and the European Clinical Trials Register from inception to 2 January 2018. Conference abstracts and references were searched to identify additional studies.

Selection criteria: 

Randomized controlled trials (RCTs) comparing any form or dose of cannabis or its cannabinoid derivatives (natural or synthetic) to placebo or an active therapy for adults (> 18 years) with UC 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 (as defined by the primary studies). Secondary outcomes included clinical response, endoscopic remission, endoscopic response, histological response, quality of life, C-reactive protein (CRP) and fecal calprotectin measurements, symptom improvement, adverse events, serious adverse events, withdrawal due to adverse events, psychotropic adverse events, and cannabis dependence and withdrawal effects. We calculated the risk ratio (RR) and corresponding 95% confidence interval for dichotomous outcomes. For continuous outcomes, we calculated the mean difference (MD) and corresponding 95% CI. Data were pooled for analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). Data were analyzed on an intention-to-treat basis. GRADE was used to evaluate the overall certainty of evidence.

Main results: 

Two RCTs (92 participants) met the inclusion criteria. One study (N = 60) compared 10 weeks of cannabidiol capsules with up to 4.7% D9-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 (N = 32) compared 8 weeks of therapy with two 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. No studies were identified that assessed cannabis therapy in quiescent UC. The first study was rated as low risk of bias and the second study (published as an abstract) was rated as high risk of bias for blinding of participants and personnel. The studies were not pooled due to differences in the interventional drug.

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% (7/29) of the cannabidiol group compared to 26% (8/31) in the placebo group (RR 0.94, 95% CI 0.39 to 2.25; low certainty evidence). Clinical response at 10 weeks was achieved in 31% (9/29) of cannabidiol participants compared to 22% (7/31) of placebo patients (RR 1.37, 95% CI 0.59 to 3.21; low certainty evidence). Serum CRP levels were similar in both groups after 10 weeks of therapy. The mean CRP in the cannabidiol group was 9.428 mg/L compared to 7.638 mg/L in the placebo group (MD 1.79, 95% CI -5.67 to 9.25; moderate certainty evidence). There may be a clinically meaningful improvement in quality of life at 10 weeks, measured with the IBDQ scale (MD 17.4, 95% CI -3.45 to 38.25; moderate certainty evidence). Adverse events were more frequent in cannabidiol participants compared to placebo. One hundred per cent (29/29) of cannabidiol participants had an adverse event, compared to 77% (24/31) of placebo participants (RR 1.28, 95% CI 1.05 to1.56; moderate certainty evidence). However, these adverse events were considered to be mild or moderate in severity. Common adverse events included dizziness, disturbance in attention, headache, nausea and fatigue. None (0/29) of the cannabidiol participants had a serious adverse event compared to 13% (4/31) of placebo participants (RR 0.12, 95% CI 0.01 to 2.11; low certainty evidence). Serious adverse events in the placebo group included worsening of UC and one complicated pregnancy. These serious adverse events were thought to be unrelated to the study drug. More participants in the cannabidiol group withdrew due to an adverse event than placebo participants. Thirty-four per cent (10/29) of cannabidiol participants withdrew due to an adverse event compared to 16% (5/31) of placebo participants (RR 2.14, 95% CI 0.83 to 5.51; low certainty evidence). Withdrawls 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 (MD -4.00, 95% CI -5.98 to -2.02). After 8 weeks, the mean change in CRP levels was similar in both groups (MD -0.30, 95% CI -1.35 to 0.75; low certainty evidence). The mean fecal calprotectin level in cannabis participants was 115 mg/dl compared to 229 mg/dl in placebo participants (MD -114.00, 95% CI -246.01 to 18.01). No serious adverse events were observed. This study did not report on clinical remission, clinical response, quality of life, adverse events or withdrawal due to adverse events.

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