Over the last decade, interest in the therapeutic potential of cannabis and its constituents (e.g. cannabidiol) in the management of inflammatory bowel diseases (IBD) has escalated. Cannabis has been increasingly approved for a variety of medical conditions in several jurisdictions around the world. In animal models, cannabinoids have been shown to improve intestinal inflammation in experimental models of IBD through their interaction with the endocannabinoid system. However, the few randomized controlled trials of cannabis or cannabidiol in patients with IBD have not demonstrated efficacy in modulating inflammatory disease activity. Cannabis may be effective in the symptomatic management of IBD. Given the increasing utilization and cultural acceptance of cannabis, physicians need to be aware of its safety and efficacy in order to better counsel patients. The aim of this review is to provide an overview of the role of cannabis in the management of patients with IBD.

Introduction The inflammatory bowel diseases (IBD), which comprise Crohn’s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated diseases of the gastrointestinal tract.1 IBD is characterized by periods of inflammatory flares, quiescence, and relapse, which places a substantial psychologic, emotional, and symptomatic burden on affected individuals.2 The incidence and prevalence of IBD globally continues to rise.3–7 The current therapeutic goals in managing patients with IBD are: a reduction in inflammation, elimination of symptoms, improvement in quality of life, and the prevention of complications.8 Advances in the understanding of the immunopathological mechanisms behind the disease have led to the development of a number of new effective therapies used in the induction and maintenance of remission of disease activity.9 These have reduced the need for surgery and hospitalizations, and have led to improved patient quality of life.10 Current therapies, however, are not effective in all patients, and patients that do respond often lose response over time11,12 Some patients also complain of symptoms even when inflammation is controlled and in remission. Cannabis may be an adjunct to medications in controlling inflammation, as well as improving a patient’s symptoms and quality of life.13 Cannabis, a drug made up of the flowers and buds of the Cannabis sativa plant, has been used therapeutically for centuries.14,15 Ancient Chinese cultures have reported use in their medical practices, dating back as early as 2700 BC.15 Although widely used recreationally during the 19th and 20th centuries, the use of medical cannabis has exploded over the last decade, as a result of mainstream cultural acceptance and legalization in several countries around the world. Cannabis contains over 100 different constituents, with Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being the most prominent and best characterized.16 These act on the endocannabinoid system (ECS),17 and have demonstrated analgesic and antinociceptive activity in several animal and human models.18–21 The primary clinical use of cannabis has been in the management of acute and chronic pain. It may be useful in reducing the use and dependence on opioids in the management of pain. The constituents of cannabis, however, also act on a number of other central and peripheral receptors, and can impact cytokine and immunoglobulin production as well as control immune cell migration.22–24 Cannabis has been demonstrated to have anti-inflammatory effects, and therefore may be useful in the treatment of a number of chronic inflammatory conditions including IBD.25,26 Patients will often turn to complementary medications, including cannabis, in the management of their IBD. Many physicians are unaware of the potential therapeutic role of cannabis, due to its relatively recent emergence and legalization for medical use.27,28 They should, however, be familiar with the its current use, evidence for a role in symptom management and disease control, as well as potential adverse effects, in order to safely advise patients. The aim of this review is to provide an overview of the role of cannabis in the management of patients with IBD. Relevant manuscripts were included after a comprehensive abstract review of the PubMed library and the Cochrane database using the keywords ‘cannabis, cannabidiol, inflammatory bowel disease, Crohn’s disease and ulcerative colitis’.

Cannabis use in patients with IBD Patients with IBD often turn to complementary medications, including various forms of cannabis, to combat symptoms related to their disease. Patients have reported using cannabis to relieve symptoms of abdominal pain, nausea, diarrhea, anorexia, as well as to improve mood and quality of life.57–59 In an anonymous questionnaire-based study, IBD patients reported that cannabis improved abdominal pain (83.9%), abdominal cramping (76.8%), joint pain (48.2%), and, to a lesser extent, diarrhea (28.6%).57 Large epidemiological studies to determine the proportion of people with IBD that use cannabis have been difficult to perform due to the legalities associated with cannabis use. Several patient-reported studies indicate that between 6.8 and 17.6% of IBD patients actively use cannabis.27,57–60 A Spanish study demonstrated that 10% of IBD patients used cannabis; however, only one-third of these patients informed their physician about active use.27 A larger internet based survey of 1666 IBD patients across the United States reported that only 12.8% had discussed use with their physician.61 A Canadian study performed in 2011 evaluated 291 patients with IBD and found that 11.6% with UC and 16% with CD were active users,58 with 51% of patients with UC and 48% of patients with CD reporting cannabis use during their lifetime. In this latter study, patients with a history of abdominal surgery, chronic analgesic use, and complementary medicine use were more likely to use cannabis for symptom relief. A large population-based study explored the patterns of cannabis use in patients with IBD.60 They demonstrated that patients with IBD were more likely to have used cannabis as compared with non-IBD controls.60 Patients with IBD also had an earlier age of onset of cannabis use (15.7 years versus 19.6 years). There does appear to be a high rate of cannabis use among younger patients with IBD, with a study in a pediatric IBD clinic (18–21 years of age) reporting that 70% of 53 patients surveyed were current or past marijuana users.62

Modes of administration There are a number of potential ways of consuming cannabis, including inhalation, oral ingestion, or through topical application. Inhalation, which includes smoking or inhaling vapors formed by local heating (‘vaping’) rapidly elevate THC levels in the blood stream, with an effect starting in 15–30 min and typically lasting 2–3 h.63 Oral preparations include ingestible oils, liquid extracts, or incorporating cannabis products with food. Consuming oral preparations results in a lower bioavailability and delayed onset of action, typically starting after around an hour and lasting for 6–8 h.64 Various topical preparations are available and are generally used for localized pain management.65 A number of factors influence cannabis absorption, including recent meals, and components of these meals, inhalation techniques, and the temperature of the vaporizer, which lead to significant variability in bioavailability.66

Cannabis as a therapeutic option for IBD Crohn’s disease A small observational study performed in Israel in 2011 was the first published report of cannabis as a therapeutic option in CD.67 Of the 30 patients reviewed, 21 demonstrated significant improvement in subjective disease activity, as defined by a ⩾ 4-point reduction in Harvey Bradshaw Index (HBI) following cannabis treatment. Cannabis use was associated with reduced need for other medications as well as surgery. Safety data was not reported in this study. The same research group performed the first randomized controlled trial of medical cannabis in CD,68 with 21 patients randomized to cannabis (twice daily cigarettes containing 115 mg of THC) or placebo. Clinical remission, as defined by a Crohn’s Disease Activity Index (CDAI) <150, was achieved in 45% in the cannabis group and 10% in the placebo group; however, this did not meet statistical significance. Of those treated with cannabis, 90% demonstrated a clinical response (decrease in CDAI of >100) and 25% were also able to stop corticosteroid therapy. Cannabis use was associated with significant improvements in quality of life, pain scores, and appetite, but did not demonstrate improvement in objective markers such as C reactive protein (CRP). There were no differences in adverse effects between groups. A larger anonymous questionnaire-based study looking at cannabis use in 313 consecutive IBD patients looked at pattern of use and subjective, beneficial, and adverse effects associated with self-administration of cannabis.57 Cannabis was used by 17.6% of patients, with reported improvements in abdominal pain, cramping, joint pain, and diarrhea. The use of cannabis for more than 6 months in patients with CD was a strong predictor for requiring surgery, with an odds ratio of around 5. Cannabis use may be providing symptomatic benefit in these patients without modulating disease activity, thereby leading to progressive disease and increased complications including surgery. The results of this study, and other questionnaire-based studies, should be interpreted with caution due to a number of inherent biases. Participation was voluntary and anonymous, which may lead to selection bias in choosing patients that did use cannabis and wanted to promote cannabis. There may be a significant reporting bias if patients over or underestimate perceived benefit and side effects. Additionally, prior clinical trials and surveys did not include colonoscopy to assess mucosal healing. Colonoscopy is necessary to differentiate whether symptoms improved due to reduced inflammatory disease activity. A more recent study investigated oral CBD in 19 patients with medically refractory CD.69 These patients were refractory to standard therapy (steroids, thiopurines, or TNF antagonists), and were randomized to receive 10 mg of oral CBD or placebo twice daily for 8 weeks. This was a negative study, with no improvement in disease activity as measured by the CDAI as well as several laboratory parameters between groups. There were, however, no significant differences in adverse effects in the treatment group as compared with placebo. This pilot study introduced the use of an oral formulation of cannabis as a therapeutic option in IBD. Further studies looking at different dosing and larger numbers of patients are required to assess efficacy in CD. Ulcerative colitis There have been even fewer clinical studies looking at cannabis as a treatment option in UC as compared with CD. The first randomized controlled trial was published in 2018 and investigated the safety and efficacy of a CBD rich botanical extract in patients with UC.70 Patients (n = 60) with mild-to-moderate ulcerative colitis, on a stable dose of mesalamine therapy, were randomized to receive a once daily oral capsule containing 50 mg CBD-rich botanical extract or placebo for 10 weeks. The CBD extract was not well tolerated, with 90% of patients reporting treatment-related adverse effects as compared with 48% receiving placebo. Adverse effects did lead to higher rates of discontinuation in the treatment group, the main side effect being dizziness, with resolution following treatment cessation. There was no difference in the primary endpoint of clinical remission (Mayo score of ⩽2 with no subscore >1) between groups (28% for CBD-extract and 26% for placebo.) There was, however, a trend toward improved quality of life scores and improvement in patients’ global impression of change based on per-protocol analysis. An abstract presentation at European Crohn’s and Colitis Organization Congress (ECCO) 2018 reported on effects of smoking cannabis cigarettes as compared with placebo in 28 patients with moderate-to-severe UC.71 Those randomized to cannabis demonstrated improved clinical disease activity scores, with no significant improvement in endoscopic disease activity scores. Biomarkers, including fecal calprotectin and CRP, however, did not change significantly. IBD-combined A prospective observational study assessed the impact of inhaled cannabis on quality of life and disease activity.72 Patients (n = 13) with long standing IBD, (11 CD and 2 UC) were prescribed cigarettes (50 g dry processed plant/month) and followed up for 3 months. Patients reported improvements in health perception (p = 0.001), social functioning (p = 0.0002), ability work (p = 0.0005), physical pain (p = 0.004), and depression (p = 0.007). There were also significant improvements in disease activity in the patients with CD, measured by the HBI as well as a significant improvement in weight. An unpublished meta-analysis of 100 patients from nonrandomized studies and randomized controlled trials up until July 2018, looking at safety and efficacy of cannabis/cannabinoids in IBD was presented at the ECCO Congress 2019.73 The authors concluded that cannabinoids were not effective in inducing remission of disease (RR = 1.29, 95% CI 0.68–2.47). They did report, however, significant differences in disease activity scores in the intervention group compared with the control group. There was improvement in symptom and quality of life scores associated with cannabinoids. The data suggest a limited efficacy of cannabis in inducing remission of disease activity. The current studies, however, are small, with various formulations, doses, and mechanisms of delivery. The main observational and randomized clinical trials are summarized in Table 1. Table 1. Summary of observational studies and clinical trials of cannabis in inflammatory bowel disease. View larger version

Safety and adverse effects The long-term safety profile of cannabis in patients with IBD has not been established. The current studies, which include use of oral and inhaled formulations, describe common side effects, including headache, sleepiness, nausea, and dizziness.67–70 The study of the CBD-rich botanical extract reported increased rates of adverse effects in patients randomized to the therapeutic product as compared with placebo; however, the majority of these were mild-to-moderate in severity.70 Adverse effects did lead to higher rates of discontinuation in the treatment group. The main adverse effect reported was dizziness, with resolution following treatment cessation. There were no significant differences in adverse effects in the other randomized trials. Cannabis use has been associated with a number of adverse short- and long-term physical and psychological health effects in studies of the general population.74 The adverse effects are exacerbated in young people. Short term The acute effects of cannabis are usually transient, lasting a few minutes to hours after consumption.75 Cannabis has a number of psychotropic effects, the main reason for its recreational use. This varies between individuals, but can include euphoria, a heightened awareness of music and color, and increased appetite. However, it can have a number of negative central effects, including impaired working and episodic memory loss/lapse.76,77 Memory impairment is usually dose dependent, with the onset of effect occurring more rapidly if inhaled rather than if consumed orally. Cannabis has also been shown increase impulsivity, reduce inhibition, and impair decision-making.78 Cannabis and its active component, THC, is known to produce transient, dose-dependent psychotic symptoms, including hallucinations and delusions, in human studies.79 Heavy use, particularly with high potency forms, and early age of onset of use, increase the risk of psychotic symptoms and development of psychotic illness.79–81 Other short-term adverse effects that have been described include panic, anxiety, tachycardia, and dry mouth.28 There has been a recent increase in the consumption of foods containing cannabis (edibles) in both the recreational and medicinal setting.82 The most significant difference between ingestion and inhalation of cannabis is the delayed onset of action associated with ingestion.64 This may lead to greater than intended consumption of the drug before it has taken effect, resulting in serious adverse effects, overdose, and even death.82–84 To promote safe use and prevent adverse effects, it is important to educate patients on how edibles affect the body. Long term Prolonged cannabis has been associated with a number of long-term neurocognitive side effects. One of the main long-term consequences is the risk of addiction. Among individuals who experiment with cannabis, 9% became dependent, with higher rates of dependence if initially consumed as a teenager.85,86 As with other addictive substances, attempting to stop may lead to withdrawal symptoms, which makes cessation difficult.87 Cannabis has also been labeled a gateway drug, with increased susceptibility to other drug addictions.88 Although long-term memory impairments have been reported, confounding factors such as baseline cognitive function, concurrent use of other cognitively impairing substances, mental health comorbidities, and age of use make a causal relationship difficult to establish.75 Functional neuroimaging studies have demonstrated subtle differences in brain activity between cannabis users and controls; however, the clinical implications of these differences are difficult to determine.89 Use during adolescence, a period of brain development, is associated with reduced functional connectivity of the brain.90,91 This is reflected in a significant decline in IQ scores in adolescents that frequently use cannabis, with a greater decline in more persistent users.92 Cannabis use has been associated with a number of mental health issues. Epidemiological research suggests chronic use increases the risk of psychoses and may exacerbate the clinical course of patients with schizophrenia.80,81,93 There has also been an association with anxiety and depression.94–96 Prolonged cannabis use is associated with a number of physiological effects. Cannabis has also been demonstrated to have detrimental effects on male and female fertility, and may also impact fetal neurodevelopment.97–99 There has also been an association with increased cardiovascular risks, including ischemic strokes and myocardial infarctions, particularly with larger doses of cannabis.100 Smoking cannabis has also been associated with chronic bronchitis and increased rates of respiratory infection.101 The most commonly reported gastrointestinal side effect is the development of cannabis hyperemesis syndrome.102,103 This syndrome, seen in chronic cannabis users, is characterized by recurrent episodes of severe nausea, intractable vomiting, and abdominal pain, with a diagnosis based on the Rome IV criteria.104,105 The pathophysiology of the syndrome remains unknown; however, there may be an underlying genetic predisposition.106 Symptomatic relief may be achieved by taking a hot shower, with resolution of the problem with cannabis cessation.107 As with any medical therapy, the use of cannabis is associated with risks and adverse effects. Physicians should be aware of these potential risks. The limited studies in IBD have not reported any serious side effects but the follow-up duration was limited. Further studies are required to determine the long-term safety profile of cannabis in the management of IBD. Cannabis in pregnancy There is very limited data exploring the effects of cannabis during pregnancy and lactation.108 Cannabinoids are small lipophilic molecules and have been demonstrated to cross the placenta in several animal models.108,109 They have also been detected in breast milk; however, concentrations are low, at only 0.8% of the maternal exposure.110,111 In comparison, alcohol passes freely into breast milk at approximately the same concentration as in maternal blood.112 There is conflicting evidence about the impact of cannabis during pregnancy, with a number of observational studies in humans confounded by inaccurate reporting in use and confounding factors associated with use that may impact pregnancy outcomes.113 Several meta-analyses suggest that cannabis use may be associated with adverse outcomes, including low birth weigh, stillbirth, and preterm delivery.114–116 There is emerging evidence that cannabis may impact neurological development, impairing brain maturation, predisposing the neonate to neurodevelopmental disorders and long-term effects on cognitive function.108,109,114 Until more evidence about the short- and long-term effects of cannabis in pregnancy is available, women should be advised not to use it during pregnancy and while breastfeeding.

Guidelines and clinical recommendations Due to the current lack of evidence for the efficacy of cannabis in IBD, clinical guidelines and recommendations to assist physicians remain limited. Two recent Cochrane database reviews that reviewed the evidence of cannabis in CD and UC, respectively, were unable to make any firm conclusions on the safety or efficacy of cannabis in IBD.117 The Canadian Association of Gastroenterology released a position statement in 2018 on the use of cannabis for several gastroenterologic and hepatologic disorders.118 They stated that cannabis does not appear to alter the course of the disease in IBD (for better or worse) based on the current evidence available. They have also recommended that medical cannabis should not replace current approved medical therapies for patients with IBD. A clinical, scientific, and regulatory review commissioned by the American Crohn’s and Colitis Foundation recently concluded that, although cannabis may help control symptoms and improve quality of life in patients with IBD, it has not been demonstrated to modify disease behavior.13 This article outlined the current legal, regulatory, and logistic hurdles in investigating medical cannabis for IBD in the United States.

Conclusion and future directions There is emerging evidence that cannabis may play a role in the management of patients with IBD. Many patients are already using cannabis to help manage symptoms associated with the disease, and physicians cannot ignore this when taking histories and managing their patients. The current studies that have explored the use of cannabis in IBD have demonstrated improvement in a number of gastrointestinal symptoms as well as patient quality of life. There has been no clear evidence, however, that cannabis modulates inflammation or improves disease activity. The majority of the current literature is retrospective observational data. The few randomized trials that have been performed are small and insufficiently powered to detect any clinically significant differences between cannabis and placebo. Large prospective randomized controlled studies with standardized preparations of cannabis and long-term follow up are required to assess the effectiveness of cannabis in IBD. There have been many regulatory obstacles in research involving medical cannabis in a number of countries around the world, including the United States. A recent review, released by the Crohn’s and Colitis Foundation (United States) has called for government and regulatory policy change to facilitate further research into cannabinoid-based therapies.13 Patients often do not report cannabis use to their treating physician. As with any drug, cannabis is associated with potential risks and long-term adverse effects. To better counsel patients, it is important for physicians managing IBD to be aware of how patients are using cannabis to manage their symptoms, the current evidence for its use, as well as potential adverse effects. In summary, cannabis may improve clinical symptoms but has not demonstrated any improvement in disease activity in IBD. The risks and benefits of use should be considered for each individual patient. Cannabis should not replace current effective therapies in IBD, but can be used as a complementary adjunct in certain patients. IBD patients who are taking cannabis should be advised against taking it if their medical and family history dictates otherwise (e.g. pregnancy, age, family history of mental illness, etc.). Further large clinical trials looking at different formulations, doses, modes of administration, and long-term safety and efficacy are required to evaluate the effectiveness of cannabis in IBD.

Acknowledgements KAS holds the Crohn’s Colitis Canada Chair in IBD Research at the University of Calgary. GGK holds the Canadian Institute of Health Research Embedded Clinician Research Chair.

Author contributions

SP conducted the literature review and wrote the draft manuscript. SP and CHS planned the manuscript outline. All authors edited the manuscript and approved the final manuscript for submission. Funding

The author(s) received no financial support for the research, authorship, and publication of this article. Conflict of interest statement

SP has no conflicts. GGK has received honoraria for speaking or consultancy from Abbvie, Janssen, Pfizer, and Takeda. He has received research support from Janssen, Abbvie, GlaxoSmith Kline, Merck, and Shire. He shares ownership of a patent: TREATMENT OF INFLAMMATORY DISORDERS, AUTOIMMUNE DISEASE, AND PBC. UTI Limited Partnership, assignee. Patent 62/555,397. 7 September 2017. KAS is a consultant to Arena Pharmaceuticals, LaSanta Botanicals Ltd and Takeda Pharmaceuticals. CHS has received honoraria for speaking or consultancy for Janssen, Takeda, Ferring, Abbvie, Pfizer, Shire and has received research support from Janssen. ORCID iD

Cynthia H. Seow https://orcid.org/0000-0002-1551-9054