In this issue of the Journal of Crohns and Colitis, Naftali and colleagues report on their most recent randomized placebo controlled trial [RCT] of cannabis in Crohn’s disease. We admire and applaud their continued efforts to try to shed light on the efficacy of cannabis in treating Crohn’s disease. Similar to their original RCT,1 we see that quality of life improvements are real and robust, but again cannabis falls short in treating inflammation. The methodology here is sound, and we commend the group for using a prescription-grade purified oil with a known composition of CBD-THC [cannabidiol-tetrahydrocannabinol] [16/4%]. This is surely a cleaner method of delivery than smoking marijuana cigarettes.
The current paper adds to the small dataset examining cannabis in Crohn’s disease.1 Although small, with only 56 patients, this has expanded over previous work which had sample sizes of 20 and 21, respectively.2,3 It is also important to point out that the current study had a mean lower Crohn’s Disease Activity Index [CDAI] than the 2013 study [282 vs. 330],2 and a lower than expected rate of current biologic use [26%] than we feel would be indicated by an average CDAI of 282. This could be explained by the relatively low absolute faecal calprotectin at study entry [139 µg/g] which may indicate relatively indolent disease activity. This study improves upon the prior RCTs by adding the objective markers Simple Endoscopic Score for Crohn’s disease [SES-CD] and faecal calprotectin as secondary end-points. Previous studies evaluating both whole cannabis and low-dose CBD included C-reactive protein [CRP], but did not find a significant difference at the end of 8 weeks of treatment.2,3 Unfortunately, in the current study, we see no significant reduction in any of the two objective markers of inflammation or endoscopic disease activity for CBD-THC oil [cannabis median calprotectin visits 1 and 3: 139 µg/g vs. 112 µg/g, CRP 1.4 mg/dl vs. 1.3 mg/dl, SES-CD 10 vs. 7; p-value not significant for all].
Previous trials have found that cannabis induces clinical remission and response at high rates compared to placebo [45% vs. 10%, 90% vs. 40%] with significant improvement in quality of life,2,3 with the same result found here including a median CDAI of 282 decreasing to 166 in the cannabis group vs. 264 to 237 in the placebo group [p = 0.038]. Importantly, the authors point out that the CDAI change is driven mainly by improvements in general wellbeing and abdominal pain, while the number of bowel movements per day was not statistically significant. Despite the negative results with regard to inflammatory markers and endoscopic improvement, we appreciate the incorporation of these markers in the trial design, which is now standard in inflammatory bowel disease [IBD] drug trials.
The topic of marijuana comes up daily in the clinic, and we know our patients are using marijuana products more and more for symptom relief.4 Cannabis use will become more common as access opens and more countries and states decriminalize and legalize the product for both medical and recreational consumption. In the USA, the majority of states have decriminalized the use of marijuana and approved medicinal use, and as of April 2021, 17 states have begun to regulate recreational use.5 While we have made significant headway over the last few decades in changing the natural history of Crohn’s disease, our current medical armamentarium is ineffective for a subset of our patient population. Unfortunately, we still see a number of patients depending on steroids, narcotics or both for relief, and they are looking for a solution. However, it remains difficult for gastroenterologists and IBD specialists to recommend cannabis based on the currently available evidence, and there remains the threat of harm from treating the symptoms and masking the underlying inflammation.4
Further research is needed to explore the effect of various CBD-THC components on the inflammatory cascade, especially considering that animal models have previously demonstrated objective improvements,6 and until we see a significant impact on biomarkers, we certainly cannot recommend cannabis as a primary therapy. The role of cannabis for symptom management as a complement to biologic therapy will continue to be debated. One may argue that cannabis can serve to free patients from narcotic use, but this may be trading one potentially addictive substance for another. We appreciate the efforts of the Israeli group, but at this point in time, we would only recommend the use of cannabis in Crohn’s disease be limited to further clinical trials.
Funding
None.
Conflict of Interest
R.J.G.: speaking fees Abbvie. A.S.C.: consulting: Janssesn, Abbvie, Takeda, Pfizer, Samsung, Arena, Grifols, Prometheus, Bristol Myers Squibb; research support: Inform Diagnostics.
Author Contributions
Both authors contributed equally.
References
