Herbal and plant therapy in patients with inflammatory bowel disease.

The use of herbal therapy in inflammatory bowel disease (IBD) is increasing worldwide. The aim of this study was to review the literature on the efficacy of herbal therapy in IBD patients. Studies on herbal therapy for IBD published in Medline and Embase were reviewed, and response to treatment and remission rates were recorded. Although the number of the relevant clinical studies is relatively small, it can be assumed that the efficacy of herbal therapies in IBD is promising. The most important clinical trials conducted so far refer to the use of mastic gum, tormentil extracts, wormwood herb, aloe vera, triticum aestivum, germinated barley foodstuff, and boswellia serrata. In ulcerative colitis, aloe vera gel, triticum aestivum, andrographis paniculata extract and topical Xilei-san were superior to placebo in inducing remission or clinical response, and curcumin was superior to placebo in maintaining remission; boswellia serrata gum resin and plantago ovata seeds were as effective as mesalazine, whereas oenothera biennis had similar relapse rates as ω-3 fatty acids in the treatment of ulcerative colitis. In Crohn's disease, mastic gum, Artemisia absinthium, and Tripterygium wilfordii were superior to placebo in inducing remission and preventing clinical postoperative recurrence, respectively. Herbal therapies exert their therapeutic benefit by different mechanisms including immune regulation, antioxidant activity, inhibition of leukotriene B4 and nuclear factor-kappa B, and antiplatelet activity. Large, double-blind clinical studies assessing the most commonly used natural substances should urgently be conducted.

Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic idiopathic inflammatory bowel diseases (IBD) involving the large bowel (UC) or the small and large bowel (CD), in which patients require both induction and maintenance treatment [1]. The conventional treatment of IBD includes the use of corticosteroids, immunosuppressants, antibiotics, and biologic agents (anti-tumor necrosis factor (TNF)-α). However, the use of these drugs is accompanied by a certain number of side effects, with some of them being quite severe [1].

The term complementary or alternative medicine (AM) refers to both diagnostic and therapeutic strategies existing outside medical centers where conventional medicine is practiced [2]. Natural products, e.g. products derived from plants and herbals, are increasingly used by IBD patients.

In this review, the authors evaluate the clinical studies concerning the natural products used by IBD patients as an alternative treatment method for either induction or maintenance treatment.

Methodology

A computerized search strategy using Medline and Embase databases up to April 2014 was implemented. The medical subject headings applied were: “alternative medicine” or “herbal medicine” and “inflammatory bowel disease”, or “Crohn’s disease”, or “ulcerative colitis”. In order to obtain information concerning the physical characteristics of the herbal investigated in the clinical studies, relevant reviews published in the international scientific literature were used. All full-length randomized, placebo-controlled or controlled against a conventional treatment clinical studies were included in the analysis. Then, studies deemed eligible for inclusion were manually searched. Studies were divided into those that have assessed the use of herbal therapy for the induction of remission and maintenance of remission in UC, and the induction of remission and prevention from operative recurrence for CD. Data collection included types of herbal administered, treatment duration, length of follow up, remission and response rates, and adverse effects.

Results

From 1993 to April 2014, we identified 27 clinical studies dealing with herbal therapy in IBD. There were 17 studies of herbal therapy in UC and 10 studies in CD, including 1,874 individuals in total (Table 1). The mean age of subjects was 43 years. No significant differences concerning the number of male and female patients participating in the trials was recorded.

Table 1

Number of clinical studies performed so far and number of patients included

The most important of the available data concerning the use of herbals and plants in the treatment of IBD patients are summarized below.

UC

So far a total number of 17 clinical studies related to the treatment of either active or inactive UC with the use of herbal products have been published. The total number of patients included was 1421. These studies compared the effectiveness of herbal treatment with either drugs used regularly by patients with UC or placebo. In a minority of studies, herbal treatment was tested while the patients were receiving their regular treatment. The number of patients included in each study varied between a few dozen to more than 200. In studies dealing with induction treatment of active disease, the duration of treatment varied between 4 and 12 weeks, while in studies dealing with maintenance treatment fluctuated between 6 and 12 months.

Treatment of active disease

The total number of studies referring to the treatment of active UC was 11 and the number of patients included was 1008 (Table 1).

Aloe vera (Xanthorrhoeaceae)

Aloe vera is a herbal preparation with significant anti-inflammatory effects. The leaves of the plant contain an abundance of phytochemical substances including acetylated mannans, polymannans, anthraquinone C-glycosides, anthrones, anthraquinones (emodin), and lectins, most of which are under intense search.

In a double-blind, randomized, placebo-controlled trial, 44 hospital outpatients with mild to moderately active UC were randomly given oral aloe vera gel or placebo, 100 mL b.i.d. for 4 weeks, in a 2:1 ratio. Oral administration of aloe vera produced a clinical response more often than placebo; it also reduced the histological disease activity and appeared to be safe [3].

This herbal seems to be effective in some proportion of patients with active UC. Further studies are necessary using different doses in larger number of patients.

Triticum aestivum (Poaceae)

Triticum aestivum, common as bread wheat, is an annual grass belonging to the Poaceae family. It can be found in the form of liquid or powder. It contains chlorophyll, aminoacids, vitamins and various enzymes. The plant can be used as food, or as a drug with unique therapeutic potentials for which, however, there is no strong scientific support. It can be found as a fresh product, tablets, frozen juice, or powder.

In a randomized, double-blind, placebo-controlled study, 23 patients with active distal UC were allocated to receive either 100 mL of wheat grass juice (Triticum aestivum), or placebo, daily, for 1 month. Ten of 11 patients in the active treatment showed endoscopic improvement in comparison with 3 of 10 in the placebo group. Treatment was associated with significant reduction in the overall disease activity index and in the severity of rectal bleeding. Apart from nausea, no other serious side effects were noticed [4].

Andrographis paniculata (Acanthaceae)

Andrographis paniculata, a plant belonging to the family of Acanthaceae, grows mainly in India και Sri Lanka, as well as in South and South-Eastern Asia.

A recent randomized, double-blind, placebo-controlled study compared the extract of Andrographis paniculata (HMPL-004) with placebo in 224 adult patients with mild to moderately active UC. Treatment with HMPL-004 in a dose of 1800 mg per day resulted in a statistically significantly better clinical response compared to placebo (60% vs. 40%; P=0.018), although the proportion of remission after 8 weeks did not differ in the two groups [5].

The second study was also a randomized, double-blind, multicenter study of an 8-week duration with parallel groups. The study showed that HMPL-004 had similar effectiveness with mesalazine (response 76% vs. 82%; remission 21% vs. 16%) in patients with mild to moderate UC. In this study, there was no difference in the proportion of endoscopic remission in the two groups after 8 weeks (28% vs. 24%) [6].

Boswellia serrata (Burseraceae)

Boswellia (Boswellia serrata) belongs to the family of trees producing resin that are well-known for their good-smelling oil. Boswellia trees have a thick trunk that produces juice rich in carbohydrates, essential oils and acids called “boswellic acids”. These acids seem to be the active component of the plant being responsible for its therapeutic capabilities.

The initial clinical studies suggested that Boswellia serrata resin could be effective in IBD. In 2002, the European Medicines Agency categorized Boswellia serrata gum resin extract in the category of “orphan drugs”. Serrata gum resin extracts could influence the immune system in many ways. Boswellia serrata represses the formation of leukotriene via inhibition of 5-lipoxygenase with the action of two boswellia acids, namely 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid [7].

In the only available study, 30 patients with UC were randomized to receive either Boswellia serrata resin (900 mg/d in 3 doses, n=20) or sulfasalazine (3 g/d in 3 doses, n=10) for 6 weeks. Remission of the disease was achieved in 14 of 20 patients who received Boswellia gum resin, compared with 4 of 10 who received sulfasalazine [8]. Larger studies are urgently needed.

Jian Pi Ling (JPL)

JPL is considered as one of the current plant treatments in patients with UC. It consists of 9 components and is available in the form of tablets containing 0.75 g of dry herbal.

In a relevant study, 153 patients with UC were randomized in 3 groups. Group I: JPL tablet with Radix Sophorae flavescentis and Flos sophorae decoction; Group II: sulfasalazine and dexamethasone; Group III: placebo and enema decoction as in group I. The rate of remission after 3 months in group 1 was significantly higher (53%) compared with the rate of remission in the two other groups (28% and 19% respectively) [9]. However, the low rate of remission achieved in the two control groups raises questions about the real value of this study’s results.

Tormentil extracts (Tormentilla erecta-Rosaceae) Potentilla erecta (Tormentilla erecta, Potentilla tormentilla widely known as tormentil or septfoil) is a plant belonging to the family of Rosaceae.

Tormentil extracts have antioxidative properties and thus, it might be used as a complementary therapy for chronic IBD. In a relevant study, 16 patients with active UC received Tormentil extracts in escalating doses of 1200, 1800, 2400 and 3000 mg/d for 3 weeks each. During therapy with 2400 mg Tormentil extracts per day, median clinical activity index and CRP improved from 8 (6 to 10.75) and 8 (3 to 17.75) mg/L at baseline to 4.5 (1.75 to 6) and 3 (3 to 6) mg/L, respectively. During therapy, clinical activity index decreased in all patients, whereas it increased during the washout period [10]. Tormentil extracts appeared safe up to 3000 mg/d.

Xilei-san

Xilei-san is a mixture of herbs of Chinese medicine that harbors significant anti-inflammatory properties. It seems to be effective in a number of inflammatory conditions including digestive disorders such as esophagitis.

In an 8-week randomized, double-blind study, the Xilei-san mixture was compared with dexamethasone enema in 35 patients with mild to moderately severe ulcerative proctitis for 12 weeks. A similarly significant clinical, histological and endoscopic response compared with the baseline values in the two groups was achieved [11].

In another controlled study, 30 patients with intractable ulcerative proctitis were randomized to receive either Xilei-san or placebo suppositories for 2 weeks. The number of patients who achieved an improvement in the clinical activity index as well as in the endoscopic and histological index, was higher in the group of Xilei-san compared with the group of placebo (P<0.04) [12]. The rate of recurrence after 6 months was lower in the arm of active treatment.

No significant side effects were observed in both studies.

Anthocyanin-rich bilberry preparation

Anthocyanins, which can be found in large quantities in bilberries (Vaccinium myrtillus) were shown to have antioxidative and anti-inflammatory effects.

In the only available study Biedermann et al [13] explored the possible therapeutic potential of bilberries in active UC. Thirteen patients with mild to moderate UC were treated with a daily standardized anthocyanin-rich bilberry preparation for 9 weeks. At the end of the 6th week 63.4% of patients achieved remission and 90.9% showed a response. A significant decrease in the Mayo score was also detected in all patients. Interestingly, the fecal calprotectin levels significantly decreased during treatment phase although an increase in the calprotectin levels and disease activity was observed after cessation of bilberry intake. No serious adverse events were observed. The results clearly indicate a therapeutic potential of bilberries in UC.

Fufangkushen colon-coated capsule (FCC)

FCC is a newly developed herbal drug for the treatment of UC patients with Chinese medicine pattern of damp-heat accumulating in the interior, consisted of Sophorae flavescentis, Sanguisorba officinalis L., Indigo naturalis, Bletilla striata and Glycyrrhiza uralensis.

In order to test the efficacy and safety of FCC in patients with active UC Gong et al [14] recently performed a double-blinded, randomized clinical trial comparing FCC with Huidi (HD, mesalazine enteric-coated tablets). In this study 320 active UC patients were assigned to two groups: 240 treated with FCC plus HD placebo treatment and 80 with HD plus FCC placebo for 8 weeks. At the 8th week, 72.5% of patients in FCC group and 65.0% of patients in HD group achieved a clinical response and 41.5% in FCC group vs. 41.25% in HD group clinical remission (no significant differences). The rate of mucosal healing at week 8 was also similar in the two groups. Similar safety profiles in the 2 groups were also seen. FCC seems to be equally effective and safe in the treatment of active UC compared with mesalazine.

Table 2 shows the results of the effectiveness of herbal and plant products administration in the response and remission rate of patients with active UC.

Table 2

Studies on herbal and plant product treatment of patients with active ulcerative colitis

Maintenance treatment of UC

So far, a small number of clinical trials have been published concerning the role of plant products in the maintenance treatment of UC patients. These studies are analyzed subsequently.

Curcumin

Curcumin is a biologically active phytochemical substance showing antioxidant, anti-inflammatory, anticarcinogenic, hypocholesterolemic, antibacterial, wound-healing, antispasmodic, anticoagulant, antitumor and hepatoprotective activities. Curcumin inhibits many cytokine pathways including interleukin (IL)-6, concurrently having a favorable safety profile. Its anti-inflammatory and antioxidant effect has been shown in numerous animal models.

Hanai et al [15] evaluated the usefulness of curcumin in 89 patients with quiescent UC. Forty-five patients received 1 g curcumin b.i.d. along with sulfasalazine or mesalamine, and 44 received placebo plus sulfasalazine or mesalamine for 6 months. Curcumin significantly improved both the clinical activity index and the endoscopic index. Recurrence rates were significantly lower in the curcumin group compared with placebo. Curcumin seems to be promising and safe medication for maintaining remission in patients with quiescent UC.

Plantago ovata (Plantaginaceae)

Plantago ovata is a small plant with characteristic flowers. The juice derived from the plant leaves, has been used in the treatment of peptic ulcer and pain accompanying inflammatory conditions. The plant has anti-inflammatory and anti-oxidative properties. It inhibits the protein kinase C, it down-regulates the expression of intercellular adhesion molecule-1 and inhibits the inflammation produced from 5-hydroxy-6,8,11,14-eicosatetraenoic acid and leukotriene B4. The enzymatic dissolution of the seeds of Plantago ovata results in the production of short chain fatty acids that have favorable effects in patients with patients with UC.

In an open clinical study, 105 patients with UC in remission were randomized to receive either Plantago ovata seeds (10 g b.i.d.), mesalazine (500 mg t.i.d.), and Plantago ovata seeds with mesalazine in the same doses. The rate of recurrence after 6 months did not differ in the three groups (40% vs. 35% vs. 30%) [16]. There were few side effects mainly constipation and abdominal bloating.

Oenothera biennis

Oenothera biennis belongs to the group of Oenothera which can be found in North America and other tropical and subtropical countries. The evening primrose oil is the main product of the plant. The main constituent of Oenothera biennis seeds is the γ-linolenic acid.

The plant has been used as maintenance treatment in patients with UC with moderate results. In a placebo-controlled study, 43 patients with UC were randomized to receive MaxEPA (n=16), super evening primrose oil (n=19), or olive oil as placebo (n=8) for 6 months plus their regular maintenance treatment with 5-aminosalicylates (5-ASA). Treatment with super evening primrose oil increased the concentrations of dihomogamma-linolenic acid (DGLA) of red cell membrane (P<0.05) and the stool form during the first 6 months, compared to MaxEPA and placebo and this difference was continued 3 months after cessation of treatment (P<0.05). Evening primrose oil could offer some benefit in patients with UC [17].

Germinated barley foodstuff (GBF)

GBF represents the final product of dryness and fermentation of barley. It is based on recipes of traditional Chinese medicine having many beneficial physiological effects. GBF, which mainly consists of dietary fiber and glutamine-rich protein, is essentially a prebiotic that can reduce the clinical activity of UC over long-term as well as short-term administration [18].

In a relevant study, 59 patients with UC in remission were divided into two groups, control group (n=37) who received conventional treatment for 12 months and GBF group (n=22) who received conventional treatment plus 20 g of GBF daily. Significantly better activity index values were seen in the GBF group at 3, 6, and 12 months compared with control group. The cumulative recurrence rate in the GBF group with steroid tapering treatment was significantly lower compared with the value in the control group. No side effects related to GBF were noticed [19].

It seems that GBF is an effective and safe herbal in the maintenance treatment of UC having also the ability to taper steroid treatment.

Extract of myrrh, dry extract of chamomile flowers and coffee charcoal

It is well known that the herbal mixture of myrrh, dry extract of chamomile flowers and coffee charcoal has anti-inflammatory and antidiarrheal properties.

In the only one so far available randomized, double-blind, double-dummy study 96 patients with inactive UC were randomized to receive either the herbal preparation or mesalazine over a 12-month period. There was no significant difference in the relapse rate between the two groups (45% in the mesalazine group and 53% in the herbal group). No significant differences were also shown in relapse-free time, endoscopy and fecal biomarkers [20]. The herbal preparation was well tolerated and showed a good safety profile.

Table 3 shows the results of clinical trials with plant products of patients with UC in remission.

Table 3

Clinical trials with plant products in patients with ulcerative colitis in remission

CD

Although the number of studies concerning the role of natural products in the treatment of active CD is quite small, their results are interesting. These studies are subsequently analyzed.

Active CD

Chios mustic gum (Pistacia lentiscus-Anacardiaceae)

Pistacia lentiscus var Chia belongs to the family of Pistacia. This tree is unique in the world because it produces a special resin (mastic gum). The mastic tree belongs to the family of Anacardiaceae. Mastic gum is a natural product produced by trees growing exclusively in the Greek island of Chios. Its aromatic and therapeutic characteristics are well-known for centuries. It contains a large number of antioxidant substances, most of which have been recently identified.

In a relevant study, the effectiveness of mastic on the clinical course and plasma inflammatory mediators of patients with active CD was evaluated. Recruited to a 4-week treatment with mastic caps (6 caps/d, 0.37 g/cap) were 10 patients and 8 controls. It was found that mastic treatment significantly decreased the CD activity index (CDAI) and the plasma levels of IL-6 and CRP [21].

In a subsequent study, the same group of investigators noticed that treating CD patients with mastic resulted in the reduction of TNF-α secretion. Migration inhibitory factor release was also significantly increased, meaning that random migration and chemotaxis of monocytes/macrophages were inhibited. It seems that mastic acts as an immunomodulator on peripheral blood mononuclear cells, acting as a TNF-α inhibitor and a migration inhibitory factor stimulator [22].

We strongly suggest that larger, double-blind, placebo-controlled studies are required in order to further clarify the role of this significant natural product in the treatment of patients with active CD.

Wormwood herb (Artemisia absinthium-Asteraceae)

Absinth wormwood is a herbaceous perennial plant with a distinctive smell of sage. It has traditionally been used to treat various digestive disorders. It is traditionally made by a distillation of neutral alcohol, various herbs, spices and water. The European Union permits a maximum thujone level of 35 mg/kg in alcoholic beverages where Artemisia species is a listed ingredient, and 10 mg/kg in other alcoholic beverages.

So far, two studies have been published concerning the possible therapeutic results of this herbal in patients with active CD. In the first one, 40 patients with CD receiving 40 mg of prednisone daily for at least 3 weeks were administered a herbal blend containing wormwood herb (3x500 mg/day) or placebo for 10 weeks. After 8 weeks, there was almost complete clinical remission in 65% patients as compared to none in the placebo group. This remission persisted until the end of the observation period. It was also noticed that wormwood had a steroid sparing effect and a positive effect on the quality of life of patients [23].

In the second study, 20 patients with active CD received dry powder of wormwood or placebo while being on their previous regular treatment. After 6 weeks, 8 of 10 (80%) of patients receiving wormwood and 2 of 10 (20%) receiving placebo achieved remission. Clinical response was noticed in 6 of 10 of the group of wormwood compared to none of the group of placebo [24]. The available data so far concerning this plant seem to be promising.

Cannabis (Cannabis sativa L. - Cannabaceae)

Cannabis sativa is an annual herbaceous plant in the Cannabis genus, a species of the Cannabaceae family. Although the main psychoactive constituent of Cannabis is tetrahydrocannabinol, the plant contains almost 60 cannabinoids. Differences in the chemical composition of Cannabis varieties may produce different effects in humans. The marijuana plant cannabis is known to improve inflammatory processes, while experimental evidence suggests that the endogenous cannabinoid system inhibits colonic inflammation, leading to the conclusion that cannabis may have a therapeutic role in IBD.

In a retrospective observational study, disease activity, use of medication, need for surgery and hospitalization rate before and after cannabis use in 30 patients (26 males) with CD was investigated. Of the 30 patients, 21 significantly improved after treatment while the need for other medication was significantly reduced. Fifteen of the patients had 19 surgeries during an average period of 9 years before cannabis use, but only 2 required surgeries during an average period of 3 years of cannabis use [25]. In another study, a comparable proportion of UC and CD patients reported lifetime or current cannabis use [26].

During the forthcoming years, the plant might be widely used in the treatment of IBD patients. Changes in the relevant legislation, as well as the use of the plant after the patients’ informed consent, would play a significant role in the adoption of this kind of treatment. It is, however, necessary to accurately confirm the safety and effectiveness of the plant by performing large clinical studies.

Boswellia serrata extract

Pilot clinical studies support the potential of Boswellia serrata gum resin extract for the treatment of IBD. Extracts from the gum resin of Boswellia serrata affect the immune system in different ways. It could suppress leukotriene formation via inhibition of 5-lipoxygenase by two boswellic acids, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid.

In a randomized double-blind study, 102 patients with active CD randomized to receive Boswellia serrata extract (H15) or mesalazine. The mean reduction in the CDAI was 90 for H15 and 53 for mesalazine [27].

Tripterygium wilfordii Hook F

Τhe traditional Chinese drug Tripterygium wilfordii Hook F (TWHF), a diterpene triepoxide, represents the main constituent of an extract obtained from Tripterygium wilfordii. Triptolide has multiple pharmacological properties (anti-inflammatory, immune modulating, antiproliferative and antiapoptotic).

In a study exploring the potential benefit of Tripterygium wilfordii, 20 patients with active CD received tablets containing T2 for 12 weeks. CDAI was significantly reduced during the first 8 weeks, while endoscopic improvement was noticed after 12 weeks. The inflammatory indices including CRP were also reduced [28].

Table 4 shows the results of the clinical studies regarding the role of plant therapy of active CD.

Table 4

Clinical studies of plant treatment of patients with active Crohn’s disease

CD: maintenance treatment

Again a small number of studies have investigated the role of plant treatment in the prevention of recurrences in patients with CD.

Boswellia serrata

In a double-blind, placebo controlled study investigating the efficacy of Boswelan in maintaining remission in CD, 82 patients were randomized to either Boswelan (n=42, 3×2 capsules/day; 400 mg each) or placebo (n=40). No differences in the two groups concerning the remission rates were noticed. Regarding safety, no disadvantages of taking the drug compared to placebo were observed [29]. This trial confirmed the good tolerability of Boswelan, although there were no significant differences versus placebo in maintenance of remission.

Tripterygium wilfordii

Two placebo controlled studies and one prospective, single-blind study, investigated the role of Tripterygium wilfordii in the prevention of postsurgical relapses in patients with CD.

In the first one 45 patients with CD were randomized to receive either Tripterygium wilfordii or mesalazine. No relapse was noticed three months after operation. Again in 6 and 12 months after the operation the clinical relapse rate did not differ in the two groups (18% vs. 22% and 32% vs. 39%, respectively). No significant differences were observed in the rate of endoscopic recurrence after 12 months (46% vs. 61%) [30].

In the second study, 39 patients with CD were randomized two weeks after enterectomy to receive either Tripterygium wilfordii (n=21) or sulfasalazine (n=18). Clinical recurrence was noticed in 6% in the Tripterygium wilfordii group compared with 25% in the group of sulfasalazine. Again, endoscopic recurrence was observed in 22% in the group of Tripterygium wilfordii compared with 56% in the group of sulfasalazine. It seems that at least numerically, Tripterygium wilfordii is superior compared with sulfasalazine in the prevention from postsurgical recurrences of CD [31].

In the third study postoperative CD patients in remission were randomized to receive 1 mg/kg Tripterygium wilfordii polyglycoside daily, orally, or 4 g 5-ASA daily, orally, for 52 weeks. Twenty-one patients received Tripterygium wilfordii polyglycoside and 18 5-ASA [32]. The results showed that clinical and endoscopic recurrences were less common in the Tripterygium wilfordii polyglycoside group (n=4) versus the 5-ASA group (n=9).

Taking into account the results of the above mentioned studies it seems that Tripterygium wilfordii polyglycoside appears to be an effective, well-tolerated drug superior to oral 5-ASA, for preventing clinical and endoscopic recurrence in postsurgical CD.

Table 5 shows the results of the studies investigating the role of herbal treatment in the prevention of relapses of CD.

Table 5

Clinical studies of plant treatment of patients with Crohn’s disease in remission

Discussion

Use of AM by the patients with IBD at least for a short period of time is quite frequent reaching a proportion of 50% while the use of herbals as treatment of either active or quiescent disease exceeds the proportion of 58% [33].

Clinical results

The available clinical studies showed that herbal treatment produces clinical remission or improvement in patients with mild or moderate IBD at least similar to that of drugs already used in the treatment of IBD patients, although a minority of studies did not noticed beneficial effects. For example, curcumin showed better results compared to placebo in the maintenance treatment of patients with UC. Other herbals, such as Aloe vera and Boswellia serrata, were effective in patients with active UC. In cases of proctitis, the wheat grass juice showed excellent results, while HMPL-004 was superior to placebo and equally effective with mesalazine in the prevention from recurrences in patients with UC. Patients with UC showed better results compared with patients with CD, although the number of clinical studies in patients with CD was quite smaller [34].

However, there are studies showing no positive results. The reasons are probably related to the poor design of studies, the small number of patients included, the variety of substances tested, the inadequate dose of the herbals, and the improper analysis and description of the results [35].

Treatment of patients with IBD either for active disease or maintenance is quite expensive. This cost could be unsustainable for most people in many countries. On the other hand, the cost of herbal therapy is probably similar or even smaller to the cost of conventional treatment of IBD.

Cellular/molecular/systemic effects of described plant preparations

A lot of clinical and especially experimental work has suggested that, individual chemical substances derived from the described plants and herbals may have antibacterial, antioxidant, antiinflammatory, and immunoreguratory properties. For example curcumin has antioxidant, anti-inflammatory, anticarcinogenic, hypocholesterolemic, antibacterial, wound-healing, antispasmodic, anticoagulant, antitumor and hepatoprotective activities [36]. Boswellia serrata has significant immunoregulatory properties. Boswellic acids (the active moiety of Boswellia) reduces the levels of TNF-α by suppressing the biosynthesis of leukotrienes via inhibition of 5-lipoxygenase [37,38]. The extracts of wormwood (Artemisia absinthium) could reduce TNF-α and other proinflammatory cytokines. Andrographis paniculata inhibits in vitro the production of TNF-α, IL-1β and nuclear factor-κB. Moreover, the polysaccharide content of herbal and plant preparations suggests that they might also have prebiotic properties. Other herbal preparations such as GBF have prebiotic characteristics that could increase luminal butyrate production by modulating the microfloral distribution [18,39].

However, we must bear in mind that the results obtained from in vitro studies of an herbal preparation are not equally effective in vivo. This is because many factors including the amount of the active substance contained in the extract as well as interactions between individual constituents could interfere with the results obtained in IBD patients.

A summary of cellular and systemic effects of the described herbal and plants are shown in Table 6.

Table 6

Cellular, molecular and systemic effects of described plant and herbal preparations

Safety of herbal treatment

Most of the published trials showed no side effects. In fact, the number and type of side effects were similar to those of placebo or mesalazine. This is quite important in patients with previous operations or patients who experienced significant side effects being on conventional treatment.

Curcumin and mastic gum probably represent the safest herbals. Curcumin is well tolerated without any serious toxicity and side effects. Several clinical studies have confirmed its safety in humans with no treatment-related toxicity up to 8,000 mg/day for 3 months. Only minor gastrointestinal adverse events, such as nausea and diarrhea, have been reported [40]. On the other hand, no side effects related to mastic gum consumption even after long-term use has been described.

Again, we must bear in mind that herbal therapy, in general, could carry risks and produce side effects similar to other forms of alternative therapy. Liver and renal failure has been described with some of them, fortunately not with those used in the treatment of IBD patients.

Toxic effects could also be associated with the inclusion of prescription medicines in some herbal preparations including corticosteroids, and glibenclamide [41]. Toxic products such as mercury, arsenic, and lead, can be found in some plant preparations.

However, the most important side effect of the use of herbal preparations is the abandonment of the drugs used in the treatment of IBD, a fact that may lead to severe or complicated IBD. On the other hand, patients with IBD initially consulting alternative doctors may be erroneously diagnosed as suffering from irritable bowel syndrome or other disease Finally, it must be stressed that the long-term safety of herbal treatment including possible mutagenicity and carcinogenicity has not adequately be explored. We suggest that future trials could combine a safe herbal product with conventional drugs thus improving treatment outcome without increasing toxicity.

A summary of the most important side effects reported so far are mentioned in Table 7.

Table 7

Safety of the main herbal and plants used in inflammatory bowel disease treatment

Concluding remarks

The available data concerning the administration of extracts derived from plants and herbals give the gastroenterologist the excuse to explain to our patients the benefits of this therapy, concurrently providing evidence-based information about their use [42]. Pharmaceutical companies must aid to the current knowledge by supporting relevant studies even if their financial gain would be much lower compared to other kinds of treatment. Both international scientific societies and government organizations should take seriously the locally available opportunities of drug development by financially supporting relevant clinical studies. It is true that the cost of treatment of IBD patients is continuously raising and herbal treatment might represent a new effective and cheap treatment method [43]. Doctors must become more tolerant and open-minded about the benefits of AM. Finally, there is a need for more essential representation of AM in under- and postgraduate medical education.