cbd oil for pouchitis

Cannabis and cannabis oil for the treatment of 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.

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.

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.

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

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.

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.

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.

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 10% (3/31) of placebo participants (RR 0.15, 95% CI 0.01 to 2.83; 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.

Topical and Systemic Cannabidiol Improves Trinitrobenzene Sulfonic Acid Colitis in Mice

Compounds of Cannabis sativa are known to exert anti-inflammatory properties, some of them without inducing psychotropic side effects. Cannabidiol (CBD) is such a side effect-free phytocannabinoid that improves chemically induced colitis in rodents when given intraperitoneally. Here, we tested the possibility whether rectal and oral application of CBD would also ameliorate colonic inflammation, as these routes of application may represent a more appropriate way for delivering drugs in human colitis.

Methods

Colitis was induced in CD1 mice by trinitrobenzene sulfonic acid. Individual groups were either treated with CBD intraperitoneally (10 mg/kg), orally (20 mg/kg) or intrarectally (20 mg/kg). Colitis was evaluated by macroscopic scoring, histopathology and the myeloperoxidase (MPO) assay.

Results

Intraperitoneal treatment of mice with CBD led to improvement of colonic inflammation. Intrarectal treatment with CBD also led to a significant improvement of disease parameters and to a decrease in MPO activity while oral treatment, using the same dose as per rectum, had no ameliorating effect on colitis.

Conclusion

The data of this study indicate that in addition to intraperitoneal application, intrarectal delivery of cannabinoids may represent a useful therapeutic administration route for the treatment of colonic inflammation.

Introduction

Inflammatory bowel diseases (IBD) affect more than 3 million people in the western world [1]. Advances in the therapy of IBD have been achieved with new immunosuppressive and immunomodulatory agents; however, current pharmacological treatment still relies on nonsteroidal and steroidal anti-inflammatory drugs, treatments that may cause severe side effects [2]. With the advent of the so-called novel biologicals (e.g. tumor necrosis factor α antibodies), new hope was sparked for a more effective treatment of IBD, yet severe side effects and tolerance associated with long-term use of these drugs have dampened these outlooks [3]. Although currently used medication can keep IBD patients in relatively long states of remission, a more effective cure with fewer side effects is a desirable aim. Cannabinoids have recently moved into the center of inflammation research. But despite the fact that Cannabis sativa has traditionally been used for centuries as an analgesic and anti-inflammatory remedy, modern pharmacological therapy of inflammation with cannabinoids is still at the beginning. A recent article has highlighted that between 33 and 50% of people suffering from IBD have been using Cannabis to relieve IBD-related symptoms [4]. In line with this, animal models of IBD largely suggest that cannabinoid compounds and activation of cannabinoid (CB) receptors significantly suppress the severity of colitis [5, 6, 7]. In addition, non-CB receptor-mediated effects of cannabinoids can also cause improvement of experimental colitis [8, 9].

A major obstacle for the pharmacological exploitation of cannabinoids lies in their psychotropic side effects. This applies particularly to cannabinoids with strong cannabinoid 1 receptor (CB1) activity, such as Δ 9 -tetrahydrocannabinol (THC) [10] but also for CB1 antagonists, such as rimonabant [11]. However, some cannabinoids, e.g. cannabidiol (CBD) and O-1602, are known to be anti-inflammatory [9, 12, 13] while being free of adverse central side effects [12, 14]. CBD has already proven effective in decreasing the severity of experimental colitis in rodents [8]. Due to its low activity at CB receptors [15, 16] and its lack of psychoactivity [17, 18], CBD could become an important candidate for the treatment of IBD. Since orally taken cannabinoids are prone to significant metabolization in the liver [19], the route of application for cannabinoids is of major importance. For instance, Sativex ® , a 1:1 mixture of THC and CBD (GW Pharma, Salisbury, UK), is given as an oromucosal spray to avoid first-pass metabolism by the liver and degradation in the intestine [20].

To address the question of the appropriate route for the application of cannabinoids in IBD treatment, we used an established mouse model of colitis (trinitrobenzene sulfonic acid [TNBS] model) and applied CBD systemically, orally and per rectum, to prevent the severity of colitis. We found that CBD not only protected from colitis when given systemically, but was also effective when given locally per rectum. Oral application of CBD, used at the same dose as per rectum, was not effective in protecting from colitis in this mouse model.

Materials and Methods

CD1 mice (males, 5–9 weeks old, 24–35 g) were purchased from Charles River (Deisenhofen, Germany) and kept in house at least for 2 weeks prior to experiments. Mice were housed in plastic sawdust floor cages at a constant temperature (22°C) and a 12-hour:12-hour light-dark cycle with free access to standard laboratory chow and tap water. Experimental procedures were approved by the ethics committee of the Austrian Federal Ministry of Science and Research (BMWF-66.010/0109-II/3b/2010) and carried out in line with the European Communities Council Directive.

Induction of TNBS Colitis

Animals were lightly anesthetized with isoflurane. TNBS (4 mg in 100 μl of 30% ethanol) was then infused into the colon through a catheter (outside diameter 1 mm) inserted 3 cm proximally to the anus. Solvent alone (100 μl of 30% ethanol) was administered in control experiments. The dose of TNBS was previously found to induce reproducible colitis with mortality rates in the published range [6].

Drugs and Pharmacological Treatments

TNBS was purchased from Sigma-Aldrich (Vienna, Austria) and CBD was provided by GW Pharma. CBD treatment was started 1 day before TNBS induction and given once daily until the end of the experiments (3 days after TNBS induction). For intraperitoneal treatment (10 mg/kg), CBD was dissolved in vehicle (ethanol, Tween 20 and sterile saline at 1:1:8). For intragastric (by gavage) and intrarectal (by use of a catheter) treatments, canola oil was used as a vehicle. Experiments were also performed with the respective vehicles.

Macroscopic Scoring and Damage Assessment

At the end of the TNBS colitis experiments, mice were killed by cervical dislocation. The colon was immediately removed, rinsed gently with saline solution, opened longitudinally along the mesenteric border and examined. Colonic damage was assessed by a semiquantitative scoring system adapted for mice in the present study [6]. Macroscopic damage was scored according to the following scale, adding individual scores for ulcer, adhesion, colonic shortening, wall thickness, and presence of hemorrhage, fecal blood or diarrhea. Ulcer: 0.5 points for each 0.5 cm; adhesion: 0 points = absent, 1 point = 1 adhesion, 2 points = 2 or more adhesions or adhesions to organs; shortening of the colon: 1 point = >115%, 2 points = >125% (based on a mean length of the untreated colon); wall thickness measured in millimeters. The presence of hemorrhage, fecal blood or diarrhea increased the score by 1 point for each additional feature.

Histology

Following macroscopic scoring, segments of the distal colon were stapled flat onto cardboard with the mucosal side up and fixed for 24 h in 10% neutral-buffered formalin. Tissue was then dehydrated, embedded in paraffin and standard hematoxylin/eosin staining was performed on 5-µm-thick sections.

Determination of Tissue Myeloperoxidase Activity

Myeloperoxidase (MPO) activity represents an index of neutrophil accumulation in the tissue and correlates with the severity of the colitis [21]. Samples of colon were weighed, immediately frozen, and stored at −80°C prior to further processing. For the determination of MPO activity, tissue was placed in 0.5% hexadecyltrimethylammonium bromide buffer (50 mg of tissue/ml; pH 6.0) and disrupted with a homogenizer (UltraTurrax ® , IKA, Germany). Hexadecyltrimethylammonium bromide (Sigma-Aldrich) is a detergent that releases MPO from the primary granules of neutrophils and enhances enzyme activity by the presence of bromide. Afterwards, the homogenate was centrifuged for 15 min at maximum speed and 4°C. Before reading MPO activity, 7 μl of supernatant was added to 200 μl of 50 mmol/l potassium phosphate buffer (pH 6.0) containing 0.167 mg/ml of O-dianisidine hydrochloride and 0.5 μl of 1% H2O2/ml. The kinetics of MPO activity was measured at 460 nm (xMark TM , Bio-Rad, Austria). A mean was calculated for the respective TNBS + vehicle-treated groups and set at 100%. Values of the CBD treatment groups are expressed as percent of the respective TNBS + vehicle-treated group.

Statistical Analysis

From every experimental group, a mean was calculated and differences of means between groups were analyzed by one-way ANOVA followed by Tukey’s post hoc test using Graph Pad Prism (Graph Pad Software, San Diego, Calif., USA). p values >0.05 were considered significant.

Results

In all treatment groups, mice lost around 10–15% of their body weights after induction of TNBS colitis; however, no differences were observed in body weights between CBD-treated (intraperitoneal, intragastric and intrarectal) and the respective vehicle-treated mice (fig. ​ (fig.1 1 ).

Graphs showing weight changes (%) in mice during TNBS colitis. No significant differences were seen between vehicle-treated TNBS mice and TNBS mice that received CBD intraperitoneally (a), intragastrically (b) or intrarectally (c). Treatment with CBD (or with the respective vehicle) was started 1 day before application of TNBS and continued once daily for 3 more days. Until the end of the experiment, mice lost about 15% of their body weight. n = 8; significances were tested by one-way ANOVA and Tukey’s post hoc test.

In accordance with Borrelli et al. [8], intraperitoneal injection of 10 mg/kg CBD (once daily) caused a significant improvement of the colitis score index and a decrease in MPO activity (fig. ​ (fig.2). 2 ). In mice treated with intraperitoneal CBD, histological sections from lesioned areas revealed less destruction of the epithelial lining, a reduction in colon thickness and less infiltration of immunocytes, as compared to intraperitoneally vehicle-treated mice (fig. ​ (fig.3). 3 ). Intragastric treatment with CBD (20 mg/kg; once daily) did not lead to an improvement of the colitis score (fig. ​ (fig.2). 2 ). The 20 mg/kg dose for the intragastric treatment was chosen because it proved effective in an inflammatory and neuropathic pain model of the rat [22]. By applying the same dose for intrarectal treatment (20 mg/kg; once daily), a small but significant improvement of the colitis score index was observed (fig. ​ (fig.2). 2 ). MPO activity was significantly decreased indicating a reduction in the severity of the inflammation (fig. ​ (fig.2). 2 ). A representative histological section from a lesioned area in the colon of intrarectally CBD-treated mice shows reduced leukocyte infiltration and partially preserved crypt architecture in comparison to intrarectally vehicle-treated mice (fig. ​ (fig.3 3 ).

Macroscopic scoring and MPO activity assays of mice with TNBS colitis. Intraperitoneal injection of 10 mg/kg CBD (once daily) caused a significant improvement of the colitis score index (a; n = 11–13) and a decrease in MPO activity (b; n = 9–10). Intrarectal application of 20 mg/kg CBD also significantly improved colitis parameters (e; n = 11) and decreased MPO activity (f; n = 11). c Intragastric treatment with CBD (20 mg/kg) did not lead to improvement of the colitis score (n = 11–12). d Differences in MPO activity were not significant (n = 8). Significances were tested by one-way ANOVA and Tukey’s post hoc test.

The pictures depict representative histological sections of lesioned areas in the colon of TNBS mice. Moderate destruction of the epithelial lining and a reduction in leukocyte infiltration is seen in intraperitoneally (IP) CBD-treated mice, as compared to intraperitoneally vehicle-treated mice. An image of a lesioned area in the colon shows that the crypt architecture of the epithelium was more preserved in intrarectally (IR) CBD-treated mice than in intrarectally vehicle-treated mice. Calibration bar = 500 μm.

Discussion

Over the last decade, cannabinoids and the endocannabinoid system (ECS) have become a hot topic in inflammation research, and evidence is multifold that cannabinoids can protect against different forms of inflammation by targeting CB receptors and other structures within the ECS. Regarding the gastrointestinal tract, cannabinoid-induced protection against experimental gastrointestinal inflammation was first shown by Massa et al. [5] in 2004 and later confirmed and further characterized by others [6, 8, 9, 23, 24]. We now know that these effects involve CB1 and CB2 receptors. Additional targeting of structures within the ECS, like the anandamide-degrading enzyme fatty acid amide hydrolase and the endocannabinoid membrane transporter, results in protection against intestinal inflammation [25]. More importantly, translational studies indicate that the ECS is activated in human IBD [26, 27], suggesting that the ECS not only plays a crucial role in animal models of IBD, but also in human gastrointestinal inflammation. Concepts need to be developed therefore, as to how the knowledge generated from basic research can be translated into humans and how the discovered mechanisms may be applied to result in future treatments of human IBD. Our present study confirms previously published studies [8] for it shows that intraperitoneal CBD protects against intestinal inflammation and we can furthermore show that not only systemically, but also topically applied CBD is protective. This represents a significant extension of our knowledge on how to apply cannabinoids since previous studies in animal models of IBD focussed on pathophysiological mechanisms and, for the ease of use, cannabinoids were applied by intraperitoneal injections. Whereas this way of application is feasible in an experimental setup, there is little doubt that such a mode of action is unlikely to be translated into future therapeutic use for humans [28]. The intraperitoneal route has advantages over the oral route as it bypasses the hepatic metabolism of the employed cannabinoids. It is known that hepatic metabolization is a limiting factor of systemic cannabinoid use [19]. Because promotion of inhaled (smoked) cannabinoids is not advisable from a health perspective, our study is of major interest as it shows for the first time that intrarectal application protects against intestinal inflammation. Intrarectal application is an easy mode of drug application, especially for patients with distal colitis, rectosigmoiditis, proctitis and pouchitis. In human use, it is also one of the preferred modes of application for other compounds like steroids and aminosalicylates [29]. Thus, our results promote the notion that a clinical investigation using CBD in patients with the above-mentioned diseases should be considered. Because CBD, as compared to other cannabinoids, has a favorable side effect profile [18], such a study seems feasible. Hepatic first-pass effects were also demonstrated for cannabinoids of other composition, such as for THC [19], but in contrast to CBD, systemic (e.g. psychotropic) effects were still prevalent [30].

In the present study, no effects of CBD were seen following oral application of 20 mg/kg, a dose that was shown to improve pain in rats caused by chronic sciatic nerve constriction and intraplantar injection of complete Freund’s adjuvant [22]. Whether higher doses of CBD or application twice a day and 3 times a day would result in observable effects remains unresolved at the moment. Also, whether rectal CBD protects against colitis by activation of local mechanisms or by systemic effects is unknown and needs to be addressed in a concomitant study. This is of additional interest as a true local effect would allow the development of e.g. slow-release formulations that may be ingested orally and then act throughout the colon, thus being helpful in patients with proximal colitis and pancolitis.

To summarize, CBD was given via 3 different routes of delivery to mice and its effect on the severity of TNBS colitis was compared. We confirm that CBD given intraperitoneally is protective, and we add that CBD given per rectum also offers protective effects, suggesting that rectal application of cannabinoids for the therapy of intestinal inflammation may be a feasible option.

The Use of Complementary and Alternative Medicine in Patients With Inflammatory Bowel Disease

Complementary and alternative medicine (CAM) includes products or medical practices that encompass herbal and dietary supplements, probiotics, traditional Chinese medicines, and a variety of mind-body techniques. The use of CAM in patients with inflammatory bowel disease (IBD) is increasing as patients seek ways beyond conventional therapy to treat their chronic illnesses. The literature behind CAM therapies and their application, efficacy, and safety is limited when compared to studies of conventional, allopathic therapies. Thus, gastroenterologists are often ill equipped to engage with their patients in informed and meaningful discussions about the role of CAM in IBD. The aims of this article are to provide a comprehensive summary and discussion of various CAM modalities and to appraise the evidence for their use.

Complementary and alternative medicine (CAM) consists of products and medical practices or disciplines that are not considered mainstream, or conventional, medicine. 1 , 2 CAM can include herbal therapy or phytotherapy, dietary supplementation, probiotics, Chinese medicinal practices (eg, herbal supplements or acupuncture), mindfulness, or other mind-body therapies. As the names imply, nonmainstream treatments used in conjunction with conventional (allopathic) medical therapy are considered complementary, whereas nonmainstream therapies used in lieu of conventional treatments are considered alternative. 2

The use of CAM has increased in popularity over the past several decades, particularly in Western societies (specifically in North America and Europe). 3 This increase in the use of CAM is particularly true in patients with chronic diseases, such as inflammatory bowel disease (IBD). 2 , 4 Discordant with this trend is most gastroenterologists’ knowledge of CAM and their ability to engage in informed discussions with patients who are interested in or who use CAM. 1 , 2 One of the major issues is the lack of well-designed, randomized, controlled trials (RCTs) studying the safety and efficacy of CAM. Furthermore, the data behind CAM vary and are based mostly on survey studies, case reports, and case series, and only a few well-designed RCTs. 5 The aims of this article are to describe some of the most commonly used CAM therapies and summarize the data presently available on their safety and efficacy in order to better prepare gastroenterologists to engage with patients in discussion of this topic.

Epidemiology of Complementary and Alternative Medicine Use in Patients With Inflammatory Bowel Disease

The estimated prevalence of CAM use in patients with IBD is high, ranging between 21% and 60%. 1 , 4 , 6 , 7 Reasons for CAM use include a desire for holistic approaches to supplement conventional therapy 2 , 8 ; the perception that herbal remedies are more natural, less toxic, or harmless; a lack of response to or undesirable side effects of conventional therapy 6 , 7 ; and the desire for more control of the disease and symptoms to improve quality of life (QOL). 3 , 9 Predictors of CAM use include psychiatric comorbidities; dissatisfaction with the patient-doctor relationship; side effects from conventional therapies; use of CAM among friends or family 8 ; vegetarianism; longer disease duration; high corticosteroid usage; female sex; and higher income, education, and socioeconomic status. 3 , 10 , 11 There is also geographic variation with regard to CAM use. 1 , 10 In the United States, CAM is more frequently used in the Mountain, Pacific, and Midwest regions compared to other parts of the country. 2

However, despite the widespread use of CAM, up to 75% of patients with IBD do not discuss their usage of CAM with their physicians. 8 , 11 Some patients regard taking vitamins and supplements as normal practices and, thus, do not disclose this use. 1 Poor patient-doctor relationships may also deter open discussion, as well as physicians’ lack of knowledge of CAM. 9 Being unaware of CAM use in IBD patients can be detrimental, as certain oral CAM therapies may have side effects, interactions, or organ-specific toxicities. 9 CAM use has also been associated with worse compliance with conventional therapies. 7 , 12

Most CAM therapies fall into one of the following main categories: (1) herbal/botanical or dietary supplements and (2) mind-body practices, including hypnosis, yoga/exercise, mindfulness, and stress reduction. The most commonly used CAM therapies include probiotics, herbs (including Chinese medicines, curcumin, and cannabis), vitamins, and fish oil. 1 , 13 Other therapies include the use of traditional Chinese practices such as acupuncture and moxibustion.

Probiotics

Probiotics are among the most popular CAM therapies and come in various forms, including single or multiple strains of bacteria and/or yeast. 1 The probiotic market has grown rapidly over the past decade. However, the current regulation of probiotics—as well as of most herbal and dietary supplements—is inadequate to protect consumers and doctors, as different formulations can vary tremendously in quality and potency. 14 Probiotics are thought to be anti-inflammatory and to impact immune-modulatory pathways, such as by downregulating the expression of Toll-like receptors and inflammatory cytokines as well as by inhibiting the phosphoinositide 3-kinase/Akt pathway and the nuclear factor κ–light chain enhancer of activated B cells (NF-κB) pathway. 15 , 16

The most robust data for the use of probiotics in IBD are for the prevention of recurrent pouchitis, an inflammatory condition of the ileal pouch–anal anastomosis (IPAA) that occurs in over 50% of patients after surgery. 17 Pouchitis is likely caused by aberrant immune responses and bacterial dysbiosis. 1 VSL#3 is the most-studied probiotic. It is a high-concentration probiotic preparation of 8 live bacterial strains: Streptococcus thermophilus, 4 strains of Lactobacilli (L paracasei, L plantarum, L acidophilus, and L delbrueckii), and 3 strains of Bifidobacteria (B longum, B breve, and B infantis). This probiotic appears to work by decreasing tumor necrosis factor (TNF)-α, interferon-γ, and matrix metalloproteinases 2 and 9. 16

Prevention of a First Episode of Pouchitis and of Recurrent Pouchitis

One RCT suggested that VSL#3 decreased the risk of developing a first episode of acute pouchitis within a year after an IPAA. 18 Forty patients were randomized to either VSL#3 (900 billion bacteria daily) or placebo immediately following an IPAA. Fewer patients receiving VSL#3 vs placebo developed their first episode of pouchitis over 12 months (10% vs 40%; P<.05). Furthermore, VSL#3 may decrease the risk of recurrent pouchitis. Mimura and colleagues reported in a small RCT (N=36) that 85% of patients taking VSL#3 at 6 g daily (300 billion bacteria/g) vs 6% of patients on placebo maintained remission after 12 months of follow-up. 19 However, not all studies have had positive findings. In a cohort of 31 patients with antibiotic-dependent pouchitis who were placed on VSL#3 6 g/day following 2 weeks of ciprofloxacin, 80% of patients stopped taking the probiotic due to recurrence or adverse effects (bloody bowel movements, constipation, bloating, gas in 2 patients). 20 The 20% of patients who continued taking VSL#3 remained in clinical remission at 8 months, although without significant improvement of endoscopy scores.

Induction of Remission in Active Mild-to-Moderate Ulcerative Colitis

There is some evidence that certain probiotics, especially VSL#3, may be effective for achieving clinical response and remission in mild-to-moderate ulcerative colitis (UC). In a RCT (N=147), more patients with active mild-to-moderate UC receiving VSL#3 (900 billion bacteria/day) at 6 weeks had 50% improvement in the Ulcerative Colitis Disease Activity Index (UCDAI) compared to those receiving placebo (32.5% vs 10.0%; P=.001). At week 12, 42.9% of patients on VSL#3 achieved remission vs 15.7% of patients in the placebo group (P<.001). 21 Similar results were reported from a RCT conducted by an Italian group around the same time. 22 A meta-analysis found that VSL#3, when added to conventional therapy at a dose of 3.6 × 10 12 colony-forming units/day, is safe and more effective than conventional therapy alone in achieving higher rates of response and remission in patients with mild-to-moderate UC. 23

A positive signal has been observed with other probiotic formulations as well. Tamaki and colleagues conducted a RCT investigating the efficacy of B longum 536 for induction of remission in active mild-to-moderate UC. 24 Although there was no difference in remission rates, UCDAI scores decreased by more points in the probiotic group vs the placebo group (3.8 vs 2.6 points; P<.01). 24 However, in a RCT using nonpathogenic strains of Escherichia coli Nissle 1917 in patients with active UC as an add-on to conventional therapies, no benefit was seen in the probiotic group. 25

Maintenance of Remission in Ulcerative Colitis

In patients with quiescent UC, the current literature suggests that probiotics may also reduce rates of relapse. 16 , 26 The only RCT studying the add-on use of VSL#3 (weight-based 450-1800 billion bacteria/day) to a 5-aminosalicylate (5-ASA) in the maintenance of remission involves a small pediatric cohort (N=29) with mild-to-moderate UC. 27 Fewer patients treated with VSL#3 (21.4% vs 73.3%) relapsed within 1 year of follow-up. At 6 months, 12 months, and time of relapse, endoscopic and histologic scores were lower in the VSL#3 group. Another RCT compared Lactobacillus GG (18 billion bacteria/day) use with 5-ASA therapy, and found no added benefit when using both therapies together in terms of relapse rate in adult patients with quiescent UC. 28 Overall, the choice of probiotic varies across existing studies, and the optimal dose, duration, and mode of administration are still unclear. 16 , 26

Crohn’s Disease

In Crohn’s disease (CD), the data on the efficacy of probiotics for inducing or maintaining remission are very limited. In a RCT of 119 patients with CD randomized to VSL#3 (900 billion bacteria/day) or placebo within 30 days after ileocolonic resection and reanastomosis, no difference in the proportion of patients with severe endoscopic lesions was observed at 90 days. 29 However, the VSL#3 group had lower mucosal inflammatory cytokine levels than the placebo group. Overall, 2 recent meta-analyses found no benefit associated with probiotics in patients with active CD or for preventing relapse, nor in patients with postoperative CD. 16 , 26

As previously discussed, probiotics vary in cost, formulation, potency, and efficacy in UC and CD, and require doses as high as 900 billion to 1.8 trillion bacteria daily. The Toronto consensus guidelines on the medical management of nonhospitalized patients with UC do not recommend probiotics to induce or maintain complete remission outside the setting of a clinical trial, attesting to the lack of larger, more robustly designed RCTs in this domain. 30 Limitations of probiotics, specifically VSL#3, include cost, the need for high potency administration to achieve efficacy, and the lack of coverage by insurance. Adverse events are rare and generally limited to bloating. 1 , 23

Herbal and Dietary Supplementation

Curcumin (Turmeric)

Curcumin, a major phytochemical active ingredient of turmeric, is derived from a rhizomatous plant (Curcuma longa) of the ginger family. Curcumin has a characteristic yellow appearance and is a popular herbal remedy among patients with IBD. It has been shown to have anti-inflammatory and antioxidative properties on human lymphocytes and gut epithelial cell lines, 31 and reduces histologic features of inflammation and colitis in mice. 32

A multicenter RCT (N=50) showed some benefit of curcumin in inducing remission in patients with active mild-to-moderate UC who had failed 5-ASA therapy. Lang and colleagues randomized patients with active mild-to-moderate UC despite oral and topical mesalamine therapy to either continued mesalamine and placebo or continued mesalamine and curcumin (3 g/day). 31 In this trial, 53.8% of patients who received curcumin vs 0% of the placebo group achieved clinical remission at week 4 (P=.01). Additionally, endoscopic remission (partial Mayo score ≤1) was observed in 38% of the curcumin group vs 0% of the placebo group (P=.043). 31 Curcumin may also be efficacious in maintaining remission in patients with UC on sulfasalazine or a 5-ASA. Hanai and colleagues randomized 89 patients with quiescent UC on sulfasalazine or a 5-ASA to receive curcumin (1 g twice daily) or placebo, and demonstrated that fewer patients in the curcumin group relapsed during 6 months of follow-up (4.7% vs 20.5%; P=.04). 33

The results of these trials should be taken with the caveat that investigators used very pure curcumin compounds. Retail brands and formulations may not be potent enough or may not be as pure. 34 Side effects of curcumin are mild and include bloating, nausea, and transiently loose stools. 31 , 35 Based on the aforementioned evidence and safety of curcumin, it can be considered as a complement to standard therapy in active and quiescent UC, but only as an additive in conventional treatment algorithms.

Cannabis (Medical Marijuana)

Marijuana is derived from the plant Cannabis sativa and has been used for centuries as a treatment for numerous ailments. It contains over 70 different cannabinoid compounds, but the 2 major active compounds include cannabinol and θ-9-tetrahydrocannabinol (THC). 1 , 36 , 37 In the United States, cannabis is a Schedule I substance, which means that it is illegal for both recreational and medicinal use, per federal law. 38 However, individual state laws have allowed marijuana for recreational use (in 9 states) and medical use (in 29 states) as of 2018.

Cannabis acts via the endocannabinoid system (ECS), which includes the cannabinoid receptors 1 and 2 (CB1, CB2). These can be activated by a variety of synthetic or plant-derived cannabinoids, as well as ligands of the ECS (anandamide and 2-arachidonoyl glycerol). 37 , 38 Animal models have shown that activation of CB1 and CB2 attenuates experimental colitis. 38 Furthermore, CB2 activation reduces reactive oxygen species production by the intestinal epithelium and decreases macrophage production of nitric oxide. 39 Patients with UC have experienced downregulation of their ECSs, with altered levels of endogenous anandamide and increased CB2 expression. 40

The use of cannabis among patients with IBD is substantial, with up to 17.6% reporting prior or current use for disease symptoms; 84% of cannabis users report that it improves abdominal pain. 41 , 42 Approximately 10% to 15% of patients with IBD report active use, mostly for relief of symptoms (nausea, abdominal pain, and diarrhea). 1 These patients tend to have more active disease and prior abdominal surgeries and tend to use chronic pain medications and other CAM therapies. 43

Small, observational, and prospective pilot studies indicate that cannabis use by patients with IBD generally improves QOL, general health perceptions, social function, and the ability to work, and may reduce corticosteroid use and Harvey-Bradshaw Index scores. 44 , 45 In a small prospective RCT, 21 patients with CD and Crohn’s Disease Activity Index (CDAI) scores over 200 who had not responded to therapy with corticosteroids, immunomodulators, or anti-TNF agents were randomized to receive cannabis, twice daily, in the form of cigarettes (115 mg of THC) or placebo (cigarettes with cannabis flower, THC extracted). 46 Clinical response (CDAI decrease of >100) was observed in 90% of the cannabis group vs 40% of the placebo group (P=.028), and there was a significant increase in QOL in the cannabis group. However, the primary outcome of clinical remission was not met in the majority of patients, as only 45% of patients in the cannabis group vs 10% of patients in the placebo group achieved clinical remission (CDAI <150; P=.43). Furthermore, cannabis did not improve C-reactive protein (CRP). However, 19 of the 21 patients were able to distinguish which group they were assigned to due to the psychotropic effects of cannabis, essentially unblinding the study.

Since this initial RCT of cannabis, 2 other RCTs have been conducted. In a recent small RCT, 20 patients with active CD on various therapies were randomized to receive cannabidiol 20 mg/day or placebo. No significant difference in CDAI score was noted between the 2 groups after 8 weeks. 47 The more recent trial, by Irving and colleagues, showed that among patients with left-sided or extensive UC stable on 5-ASAs, a cannabidiol-rich botanical extract was superior to placebo in improving QOL outcomes, although remission rates at 10 weeks were similar between the 2 groups. 48

Aside from the lack of objective evidence that marijuana decreases inflammation in IBD, there are also legal and psychosocial risks involved with its use, particularly among younger patients. 49 Side effects of marijuana use include confusion, ataxia, dizziness, nausea, and vomiting. 42 Chronic use is associated with cognitive impairments and deficits in motivation, learning, and memory, as well as increased risk of motor vehicle crashes and decreased fertility. 38 Furthermore, the use of cannabis for more than 6 months at any time was a strong predictor for surgery in patients with CD, comparable to tobacco smoking. 42 Thus, we cannot recommend the use of cannabis in patients with IBD outside of clinical trials until studies emerge showing that it improves clinical and endoscopic outcomes and its safety is established.

Fish Oil

Fish oil is typically derived from oily fishes, such as tuna, salmon, mackerel, or sardines. The main components behind its potential therapeutic effects include omega-3 polyunsaturated fatty acids (n-3 PUFAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), the latter 2 being the main bioactive forms synthesized from the precursor n-3 PUFA α-linolenic acid. 50 , 51 Recently, n-3 PUFAs have been implicated in favorable shifts in the gut microbiota, including decreases in Faecalibacterium and an increase in Bacteroidetes. 50

Two large, well-designed trials studying the role of n-3 PUFAs in CD (EPIC-1 and -2 [Epanova Program in Crohn’s Study 1 and 2]) had negative results. 52 These trials found that treatment with 4 g/day of n-3 PUFAs was not better than placebo for preventing relapse in patients with quiescent CD. In patients with UC, the evidence is mixed. Although 1 study found that n-3 PUFA supplementation in patients with mild-to-moderate UC decreased corticosteroid requirement, its efficacy on prevention of relapse in patients in remission is debatable. 53 A RCT in patients with quiescent UC demonstrated that n-3 PUFA supplementation (γ-linolenic acid 1.6 g, EPA 270 mg, DHA 45 mg, daily) was no better than placebo in preventing relapse during 12 months of follow-up. 54 However, a recent RCT examined a cohort of patients in clinical remission (partial Mayo score <2) but with fecal calprotectin (FC) at least 150 µg/g, and randomized patients to receive EPA (1 g twice daily) or placebo. 55 The researchers found that 63.3% of patients receiving EPA vs 13.3% of patients receiving placebo had at least a 100-point reduction in FC (P<.001), and 76.7% of patients receiving EPA (vs 50% of patients receiving placebo) maintained remission (odds ratio, 3.29; 95% CI, 1.08-9.95).

Fish oil is generally safe, although many patients experience fishy breath odors. 1 With the lack of evidence for its efficacy in CD and mixed evidence in patients with UC, we do not recommend use of fish oil to maintain remission in IBD. However, we recognize that fish oil is generally safe and commonly used by the population at large for its known benefits in various cardiovascular diseases such as hyperlipidemia. 50

Chinese Herbal Medicine

Traditional Chinese medicine (TCM) is one of the most developed branches of CAM in the world. TCM encompasses the application of various herbal agents and has been used for thousands of years. 6 , 56 There have been several recent RCTs of 2 agents in particular.

Andrographis paniculata, a member of the plant family Acanthaceae, is an herbal remedy used in China and many other Asian countries. 57 In a well-designed, multicenter RCT of patients with active mild-to-moderate UC, its extract, HMPL-004, produced similar rates of clinical remission, response, and endoscopic remission when compared with 5-ASAs at 8 weeks. 58 In another RCT, HMPL-004 was compared to placebo and was found to be superior in producing significantly higher rates of clinical response. 59 In these 2 trials, the most common adverse events were abdominal pain, diarrhea, and headache. 58 , 59 However, the frequency of adverse events was similar in both the treatment and control groups.

Indigo naturalis (IN, also known as Qing-Dai) is an herbal medicine extracted from indigo plants (ie, Indigofera tinctoria) and used predominantly in China. 60 It has been used as an antipyretic and as a hemostatic agent for centuries in TCM. 5 The anti-inflammatory effect of IN is thought to be due to inhibition of TNF-α, interleukin (IL)-1 and -6, and NF-κB, as well as promotion of IL-22 production. 61 In rat models with dextran sodium sulfate–induced colitis, IN reduced myeloperoxidase activity and expression of inflammatory cytokines while increasing expression of colonic mucosal repair–related cytokines and proteins. 62

The largest well-designed, multicenter RCT evaluated the benefit of IN among 86 patients with active UC (Mayo score ≥6) refractory to conventional treatments. Those patients randomized to receive a daily dose of IN (doses of 0.5 g, 1.0 g, or 2.0 g) for 8 weeks had significantly higher rates of clinical response, remission, and mucosal healing vs patients in the placebo group. 60 Side effects included diarrhea, abdominal pain, nausea, vomiting, and headaches. Mild liver dysfunction was also observed in 10 patients who received IN. The trial was terminated early due to a report of a patient with UC (outside of the trial) who developed pulmonary arterial hypertension (PAH) after ingesting IN for 6 months. Thus, despite promising results, the authors cautioned the use of IN because of the potential for adverse events such as PAH and liver dysfunction.

A summary of evidence and recommendations involving select probiotic and oral dietary or herbal supplementation is shown in Table 1 .

Table 1.

Summary of Evidence and Recommendations Regarding Select Probiotic and Oral Dietary or Herbal Supplementation for IBD Patients

Prevention of initial pouchitis: VSL#3 decreases risk for developing first episode of pouchitis 1 year after IPAA (1 RCT) 18

Maintenance of remission in pouchitis: Evidence supporting VSL#3 for maintenance of remission in recurrent or refractory pouchitis after induction of remission with antibiotics (2 RCTs) 19 , 20

Active mild-to-moderate ulcerative colitis: Evidence supporting VSL#3 for induction of remission (2 RCTs) 21 , 22

Quiescent ulcerative colitis: Evidence supporting VSL#3 for maintenance of remission along with 5-ASA (1 pediatric RCT, no adult RCT) 27

Limited evidence supporting efficacy 16 , 29

Reasonable to use

Prevention of pouchitis after IPAA: 900 billion bacteria daily

Prevention of recurrent pouchitis: 1.8 trillion bacteria daily

Can consider use with conventional therapy in active mild-to-moderate and quiescent ulcerative colitis, but not as monotherapy (Toronto consensus)

Active mild-to-moderate ulcerative colitis: 900 billion to 3.6 trillion bacteria daily as add-on therapy

Maintenance of remission in ulcerative colitis: At least 1.8 trillion bacteria daily (extrapolated from pediatric RCT) 27

Active mild-to-moderate ulcerative colitis: Evidence supporting benefit in patients failing oral or topical 5-ASAs (1 RCT) 31

Quiescent ulcerative colitis: Evidence supporting use in patients on sulfasalazine or 5-ASA (1 RCT) 33

Reasonable to use for both active and quiescent ulcerative colitis in addition to conventional therapy

Induction of remission: 3 g/daily + standard therapy

Maintenance of remission: 2-3 g/daily + standard therapy

Improves QOL but no difference in remission rates in patients with quiescent ulcerative colitis (small, observational, and prospective pilot studies 44 , 45 and 2 RCTs 46 , 48 )

Similar rates of remission when cannabis added on to 5-ASA in stable ulcerative colitis patients 48

In 1 RCT, more patients (initial CDAI >200) with clinical response in cannabis vs placebo group, but no difference in clinical remission rates, no changes in inflammation (CRP), and increased QOL 46

Not recommended outside of clinical trial

May decrease corticosteroid requirement (1 RCT), 53 but does not prevent relapse (2 RCTs) 53 , 54

Decreases fecal calprotectin, may help maintain remission (1 RCT) 55

Not better than placebo for prevention of relapse (2 RCTs) 52

Active mild-to-moderate ulcerative colitis: Similar rates of clinical response, remission, and endoscopic remission vs 5-ASAs (1 RCT) 58 ; superior to placebo in producing higher rates of clinical response (1 RCT) 59

Quiescent ulcerative colitis: Limited evidence for maintenance of remission

Awaiting phase 3 studies

Active mild-to-moderate ulcerative colitis: significantly higher rates of clinical response, remission, and mucosal healing vs placebo (1 RCT) 60

Not recommended due to early RCT termination after report of a community case of pulmonary arterial hypertension

5-ASA, 5-aminosalicylate; CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; IBD, inflammatory bowel disease; IPAA, ileal pouch–anal anastomosis; QOL, quality of life; RCT, randomized, controlled trial.

Acupuncture and Moxibustion

Acupuncture and moxibustion are therapeutic Chinese practices that have been used for thousands of years for numerous ailments. 63 Acupuncture is the practice of placing thin needles into the skin at certain acupoints to achieve a desired benefit. 64 One variation of this practice is to use small, electrical currents at certain frequencies applied through the acupuncture needles (electroacupuncture). 65 Moxibustion is the practice of burning dried mugwort (moxa) cones on acupoints (or other parts of the body) to generate warmth stimulation. Sometimes different herbs are added to the burning cones to reach a certain desired effect; this practice is called herb-partitioned moxibustion (HPM). 64

There has been much research looking at the mechanisms of action of acupuncture and moxibustion in rat models of colitis. HPM was noted to promote repair of damaged colonic tissue and secretion of mucin in rats with colitis, and this response was correlated with an increased number of moxa cones and frequency of therapy. 66 Bao and colleagues examined the effect of acupuncture and moxibustion (with no control group) on patients with quiescent CD. 65 Both groups underwent pre- and postintervention resting-state functional magnetic resonance imaging of the brain. Both groups had reduced CDAI values, but the 2 therapies varied in how they changed brain connectivity and perhaps symptomology. 65

One study randomized 92 patients with active CD not on any conventional therapy (CDAI 151-350) to acupuncture with HPM (treatment) or wheat bran– partitioned moxibustion with superficial acupuncture (control). This RCT found that patients in the treatment group had greater reductions in CDAI (primary endpoint) as well as lower CRP and lower histopathology scores (secondary endpoints). 67 Another study randomized 51 patients with active CD (CDAI >150) to receive either acupuncture or control (sham acupuncture points) for 12 weeks. 68 The mean CDAI score (primary endpoint) decreased by 87 points in the treatment group vs 39 points in the control group (P=.003).

A meta-analysis of English and Chinese RCTs reported that the overall efficacy of acupuncture alone, moxibustion alone, or acupuncture combined with moxibustion (without sulfasalazine) was greater than the efficacy of oral sulfasalazine monotherapy for the treatment of UC. 69 However, there was low heterogeneity among the studies and low methodologic quality. Furthermore, many of these studies varied in the use of acupuncture and moxibustion sites and outcomes.

Acupuncture and moxibustion are generally safe and well tolerated. Adverse events include small, local superficial hematomas; mild bleeding; infections; and mild superficial burns (only with moxibustion). 64 Although the current evidence of acupuncture and moxibustion is promising in human RCTs, limitations such as low-quality methodology, lack of blinding, and variance in endpoints do exist in studies published in English. Thus, it is difficult to make recommendations as to the frequency and duration of acupuncture and moxibustion. However, these therapies can be considered as complements to conventional therapy in the right patient.

Cognitive-Physical (Mind-Body) Therapies

Mind-body therapies encompass an array of cognitive or psychodynamic therapies, stress management or relaxation, mindfulness, hypnosis, yoga, or exercise-based practices. 1 , 4 It is well known that psychological stress and IBD are related, and many patients with IBD have higher rates of depression, anxiety, and stress, as well as lower QOL than patients without IBD. 70 , 71 Cognitive-physical therapies are noted to be very common among patients with IBD. A Swedish study found that up to 21% of patients with IBD use massage therapy, 15.3% practice relaxation or meditation techniques, 8% engage in yoga, and 0.6% have tried hypnosis. 72

Cognitive Techniques and Therapies

The evidence on the efficacy of cognitive behavioral therapy (CBT) in patients with IBD is mixed, and existing studies vary widely on endpoints. A recent RCT (N=118) found that CBT improved disease-specific QOL based on self-reported questionnaires and lowered rates of depression and anxiety. 73 In a study of 176 patients with UC and CD, CBT plus standard therapy vs standard therapy alone did not influence the course of IBD (as measured by changes in CDAI, Simple Clinical Colitis Activity Index, CRP) over 24 months of follow-up. 74 A recent meta-analysis found that psychological therapies—particularly CBT—might have small short-term benefits on depression scores and QOL, although it noted the lack of well-designed RCTs in this domain. 75 CBT did not have any effect on disease activity indices when compared with control groups.

Another type of mind-body therapy is the practice of mindfulness. In a RCT, 60 patients with UC and CD were randomized to receive mindfulness-based stress reduction intervention or control. The mindfulness intervention included a mental body scan, sitting and walking meditations, yoga, group discussions, and sharing of experiences. Patients receiving the mindfulness intervention had significantly higher improvements in anxiety and QOL. Six months after intervention, reductions in depression and improvements in QOL were maintained. 76 No significant differences in FC, serum cytokines, or CRP were noted in another RCT employing mindfulness in patients with UC in remission. 77

Gut-directed hypnotherapy has been shown to decrease the risk of disease relapse in patients with UC in remission. In a single-center RCT conducted by Keefer and colleagues, 54 patients with quiescent UC were randomized to 7 sessions of gut-directed hypnotherapy or attention control (encouraged questions, motivational interviewing), and were followed for 1 year. 78 A higher proportion of patients in the group receiving hypnotherapy stayed in clinical remission vs placebo (68% vs 40%; P=.04). 78 Although this is the only RCT studying hypnotherapy in IBD to date, 79 the established efficacy of this therapy in improving gastrointestinal (GI)-related symptoms among patients with irritable bowel syndrome (IBS) suggests a potential adjunctive role in patients with both IBS and IBD. 80

Yoga, another type of mind-body therapy, has also been studied in patients with UC. Cramer and colleagues conducted a RCT of 77 patients with UC in remission but impaired QOL, who were randomly assigned to yoga (12 supervised weekly sessions, 90 minutes each) or to read self-care advice. 81 Patients practicing yoga had higher disease-specific QOL vs those reading self-care advice at 12 and 24 weeks. 81 A RCT studying yoga in patients with quiescent UC and CD saw improvements in anxiety and abdominal pain, but no difference in markers of immune response. 82

Exercise

Exercise is linked to higher QOL, 83 improved bone mineral density, 84 and lower rates of relapse in both patients with UC and CD. 85 , 86 Potential mechanisms of benefit include an increase in IL-6 release during exercise, which has been shown to increase glucagon-like peptides involved in the repair of damaged intestinal mucosa. 87 In animal models of colitis, exercise decreases expression of proinflammatory cytokines such as TNF-α and IL-1, and increases expression of IL-6 and -10. 85 However, there are many potential barriers for patients with IBD to exercise. These include fatigue, joint pain related to arthritis or arthropathy, abdominal pain, diarrhea, or fecal urgency. 85 Although the overall benefits of exercise and the universally safe profile of most exercise regimens are clear, excessive exercise may be detrimental and perhaps dangerous, especially in patients with more moderate or severe disease activity and sequelae of chronic disease (eg, anemia, osteoporosis). Exercise is probably best for patients in remission.

Overall, cognitive and physical or mind-body therapies are safe complements to conventional therapies. There is abundant evidence for their efficacy in improving QOL, depression, and anxiety in patients with IBD ( Table 2 ). However, little evidence indicates a positive impact on inflammation or disease activity indices.

Table 2.

Summary of Evidence and Recommendations Regarding Select Chinese Practices and Cognitive-Physical (Mind-Body) Therapies for IBD Patients

Active mild-to-moderate ulcerative colitis: Some evidence suggesting superiority to oral sulfasalazine monotherapy, although limited due to low methodologic quality 69

May decrease CDAI and CRP (2 RCTs) 67 , 68

Can consider as a complement to conventional therapy due to overall safety profile

Evidence on efficacy of CBT points toward some improvements in QOL and lower rates of depression and anxiety (1 RCT) 73 , 75

CBT does not influence course of IBD or changes in CDAI, SCCAI, or CRP (1 RCT) 74

Can consider as a complement to conventional therapy for improving QOL, anxiety, and depression

Evidence indicates improvements in QOL, anxiety, and depression (1 RCT) 76

No improvements in fecal calprotectin, serum cytokines, and CRP were noted (1 RCT) 77

Can consider as a complement to conventional therapy for improving QOL, anxiety, and depression

Gut-directed hypnotherapy increases clinical remission in patients with quiescent ulcerative colitis (1 RCT) 78

Can consider as a complement to conventional therapy for improving symptoms

Improves QOL, anxiety, and abdominal pain, but has no effect on disease activity (2 RCTs) 81 , 82

No difference in inflammatory markers 82

Can consider as a complement to conventional therapy for improving QOL and anxiety

Associated with higher QOL (1 RCT) 83

Improves bone mineral density (1 RCT) 84

Predicts lower rates of relapse (1 prospective study) 86

Can consider as a complement to conventional therapy for improving QOL and bone density

Exercise regimen should be individually tailored; avoid strenuous exercise in patients with more than mild active disease activity.

CBT, cognitive behavioral therapy; CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; IBD, inflammatory bowel disease; QOL, quality of life; RCT, randomized, controlled trial; SCCAI, Simple Clinical Colitis Activity Index.

Holistic or Comprehensive Health Wellness Retreats

Given the popularity and high prevalence of CAM use among patients with chronic diseases such as IBD, health wellness resorts or retreats have become increasingly popular. Using a combination of search terms such as IBD, health wellness, retreat, or GI in a standard search engine, we were able to find a number of health wellness resorts for patients with IBD. Some of these retreats are aimed at health wellness in general, whereas others specifically target patients with chronic diseases, such as autoimmune disorders, arthritis, cardiopulmonary diseases, IBS, and IBD. Benefits include relaxation, stress reduction, and exposure to mind-body therapies. Risks include cost, exposure to sham therapies, herbalmedication interactions, excessive laboratory or imaging testing, misinterpretation of these tests, nonadherence to conventional therapy, and exposure to endemic infections and diarrheal diseases.

Conclusion

CAM use is very common among patients with IBD and spans an array of therapies, including herbal remedies, probiotics, and cognitive-physical (mind-body) practices. Although many types of CAM are generally safe, issues of purity, contamination with toxic metals, lacing with prescription drugs, and side effects of some traditional Chinese herbal remedies must be considered. Furthermore, larger well-designed RCTs are needed to validate specific CAM therapies in order for doctors to incorporate them into their traditional treatment algorithms.

It is important for gastroenterologists to ask all patients about CAM use. In addition to maintaining a good doctor-patient relationship, providing informed guidance will help set realistic, evidence-based expectations about particular therapies. Although the majority of patients regard CAM as more natural, it is not necessarily better or safe. Side effects of the CAM of interest should be reviewed. Ultimately, the goal should be to recognize CAM as having a potential supplemental role—but not an alternative one—to the conventional armamentarium for the treatment of IBD.