Herbal and plant therapy in patients with inflammatory bowel disease

Abstract

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.

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© 2015 Hellenic Society of Gastroenterology www.annalsgastro.gr
Annals of Gastroenterology (2015) 28, 210-220
REVIEW
Herbal and plant therapy in patients with inammatory
boweldisease
Aikaterini Triantafyllidia, Theodoros Xanthosa, Apostolos Papaloisb, John K. Triantallidisc
University of Athens Medical School; ELPEN Pharma; Iaso General Hospital, Athens, Greece
Abstract e use of herbal therapy in inammatory bowel disease (IBD) is increasing worldwide. e aim
of this study was to review the literature on the ecacy 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 ecacy of herbal therapies in IBD is promising. e
most important clinical trials conducted so far refer to the use of mastic gum, tormentil extracts,
wormwood herb, aloe vera, triticum aestivum, germinated barley foodstu, 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 eective 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 benet by dierent
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.
Keywords Alternative medicine, inammatory bowel disease, herbal medicine, Crohn’s disease,
ulcerative colitis
Ann Gastroenterol 2015; 28 (2): 210-220
Introduction
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic
idiopathic inammatory 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]. e 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 eects, with some of them being quite severe [1].
e 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,
aMSc Cardiopulmonary Resuscitation, University of Athens Medical
School (Aikaterini Triantafyllidi, eodoros Xanthos); bExperimental-
Research Laboratory ELPEN Pharma (Apostolos Papalois);
cInammatory Bowel Disease Unit, “IASO General” Hospital (John K.
Triantallidis), Athens, Greece
Conict of Interest: None
Correspondence to: Prof. John K. Triantallidis,
354 Iera Odos, Haidari, 12461, Greece,
e-mail: jktrian@gmail.com
Received 14August 2014; accepted 3November 2014

Herbal therapy of IBD 211
Annals of Gastroenterology 28
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 identied 27 clinical studies
dealing with herbal therapy in IBD. ere were 17 studies of
herbal therapy in UC and 10 studies in CD, including 1,874
individuals in total (Table1). e mean age of subjects was
43 years. No signicant dierences concerning the number
of male and female patients participating in the trials was
recorded.
e 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. e total number of patients
included was 1421. ese studies compared the eectiveness
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. e 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 uctuated
between 6 and 12months.
Treatment of active disease
e 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 signicant anti-
inammatory eects. e 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 oen than placebo; it also reduced the
histological disease activity and appeared to be safe [3].
is herbal seems to be eective in some proportion of
patients with active UC. Further studies are necessary using
dierent 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. e plant can be used as food,
or as a drug with unique therapeutic potentials for which,
however, there is no strong scientic 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 signicant reduction in the overall disease activity index
and in the severity of rectal bleeding. Apart from nausea, no
other serious side eects 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 signicantly better
clinical response compared to placebo (60% vs. 40%; P=0.018),
although the proportion of remission aer 8 weeks did not
dier in the two groups [5].
e second study was also a randomized, double-blind,
multicenter study of an 8-week duration with parallel groups.
e study showed that HMPL-004 had similar eectiveness
with mesalazine (response 76% vs. 82%; remission 21% vs.
Table 1 Number of clinical studies performed so far and number of
patients included
Disease Number
of studies
Number
of patients
UC (active disease) 11 1008
UC (maintenance treatment) 6 413
CD (active disease) 6 222
CD (post-operative maintenance treatment) 4 231
Tot al 27 1874
UC, ulcerative colitis; CD, Crohn’s disease

212 A. Triantafyllidi et al
Annals of Gastroenterology 28
16%) in patients with mild to moderate UC. In this study, there
was no dierence in the proportion of endoscopic remission in
the two groups aer 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”. ese acids seem to be the active component of the plant
being responsible for its therapeutic capabilities.
e initial clinical studies suggested that Boswellia serrata
resin could be eective 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 inuence 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 avescentis
and Flos sophorae decoction; Group II: sulfasalazine and
dexamethasone; GroupIII: placebo and enema decoction as in
groupI. e rate of remission aer 3months in group1 was
signicantly 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 signicant anti-inammatory properties. It seems to
be eective in a number of inammatory 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 signicant 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. e 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]. e rate of recurrence aer 6months was lower
in the arm of active treatment.
No signicant side eects 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-inammatoryeects.
In the only available study Biedermann et al [13] explored
the possible therapeutic potential of bilberries in active UC.
irteen 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signicant decrease
in the Mayo score was also detected in all patients. Interestingly,
the fecal calprotectin levels signicantly decreased during
treatment phase although an increase in the calprotectin levels
and disease activity was observed aer cessation of bilberry
intake. No serious adverse events were observed. e 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 avescentis,
Sanguisorba ocinalis L., Indigo naturalis, Bletilla striata and
Glycyrrhiza uralensis.
In order to test the ecacy 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 signicant dierences). e rate of
mucosal healing at week 8 was also similar in the two groups.
Similar safety proles in the 2 groups were also seen. FCC
seems to be equally eective and safe in the treatment of active
UC compared with mesalazine.

Herbal therapy of IBD 213
Annals of Gastroenterology 28
Table2 shows the results of the eectiveness of herbal and
plant products administration in the response and remission
rate of patients with active UC.
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. ese studies are analyzed
subsequently.
Curcumin
Curcumin is a biologically active phytochemical substance
showing antioxidant, anti-inammatory, 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 prole. Its anti-inammatory and antioxidant eect has
been shown in numerous animal models.
Table 2 Studies on herbal and plant product treatment of patients with active ulcerative colitis
Author/
year
CAM No of
patients
Comparisons Treatment
duration
Remission/response
rate in the active
treatment
Remission/
response rate
in the control
treatment
Conclusion
Sandborn
etal, 2013
HMPL-004 224 Placebo 8 weeks 45 & 60
34 & 38
40
25
HMPL-004 at a dose of
1,800 mg/d achieved
clinical response better
than placebo
Biedermann
etal, 2013
Anthocyanin-
rich bilberry
preparation
13 No comparative
arm
9 weeks 63.4% remission,
90.9% response
No comparative
arm
e results indicate a
therapeutic potential of
bilberries in UC
Zhang etal,
2013
Xilei-san enema 35 Dexamethasone
enemas
8 weeks - - Xilei-san enemas
are comparable to
dexamethasone enemas
An alternative drug in the
treatment of active UP
Fukunaga
etal, 2012
Xileisan
suppositories
30 Placebo
suppositories
2 weeks Higher number
of patients in
remission vs placebo
Signicant clinical and
endoscopic ecacy of
Xilei San in patients with
intractable U proctitis
Gong etal,
2012
Fufangkushen
colon-coated
capsule (FCC)
320 (240
with FCC
plus HD)
Huidi (HD)
mesalazine
enteric-coated
tablets 80 with HD
plus FCC placebo
8 weeks 72.5% of patients
in FCC group
(170/234)
65.0% of patients
in HD group
(52/80) had
achieved a clinical
response (P>0.05)
Compared with HD, FCC
is similarly eective and
safe in the treatment of
active UC
Tan g etal,
2011
HMPL-004 120 Mesalazine 8 weeks 21 & 76 respectively 16 & 82
respectively
Ecacious alternative to
mesalazine in active UC
Huber R
etal, 2007
Tormentil extracts
in escalating doses
of 1200, 1800, 2400
and 3000 mg/d
16 - 3 weeks During therapywith
2400 mg TE/d, CAI
and CRP improved
and CAI decreased
in all patients
- TE appeared safe up to
3000 mg/d
Langmead
etal, 2004
Aloe vera 44 Placebo 4 weeks 30 7 Oral aloe vera produced
a clinical response more
oen than placebo and
reduced the histological
disease activity
Ben-Arye
etal, 2002
Triticum aestivum 23 Placebo 4 weeks 91 42 Eective and safe as a single
or adjuvant treatment of
active distal UC
Gupta etal,
2001
Boswellia serrata 30 Sulfasalazine 6 weeks 70 40 Boswellia serrata gum resin
could be eective in the
treatment of UC
Chen etal,
1994
Jian Pi Ling (JPL)
tablet
153 Sulfasalazine (S),
Placebo (P)
90 days 53 28 (S)
19 (P)
JPL seems to be the best
therapeutic program
FCC, fufangkushen colon-coated capsule; JPL, Jian Pi Ling tablet; UC, ulcerative colitis; CRP, C-reactive protein; CDAI, Crohn’s disease activity index

214 A. Triantafyllidi et al
Annals of Gastroenterology 28
Hanai et al [15] evaluated the usefulness of curcumin in
89 patients with quiescent UC. Forty-ve 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 signicantly improved both the clinical
activity index and the endoscopic index. Recurrence rates
were signicantly 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 owers.
e juice derived from the plant leaves, has been used
in the treatment of peptic ulcer and pain accompanying
inammatory conditions. e plant has anti-inammatory
and anti-oxidative properties. It inhibits the protein kinase
C, it down-regulates the expression of intercellular adhesion
molecule-1 and inhibits the inammation produced from
5-hydroxy-6,8,11,14-eicosatetraenoic acid and leukotriene B4.
e enzymatic dissolution of the seeds of Plantago ovata results
in the production of short chain fatty acids that have favorable
eects 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. e rate of recurrence aer
6months did not dier in the three groups (40% vs. 35% vs.
30%) [16]. ere were few side eects 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. e evening primrose oil is the main
product of the plant. e main constituent of Oenothera biennis
seeds is the γ-linolenic acid.
e 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
rst 6 months, compared to MaxEPA and placebo and this
dierence was continued 3months aer cessation of treatment
(P<0.05). Evening primrose oil could oer some benet in
patients with UC [17].
Germinated barley foodstu (GBF)
GBF represents the nal product of dryness and fermentation
of barley. It is based on recipes of traditional Chinese medicine
having many benecial physiological eects. GBF, which
mainly consists of dietary ber 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.
Signicantly better activity index values were seen in the GBF
group at 3, 6, and 12months compared with control group.
e cumulative recurrence rate in the GBF group with steroid
tapering treatment was signicantly lower compared with the
value in the control group. No side eects related to GBF were
noticed [19].
It seems that GBF is an eective and safe herbal in the
maintenancetreatment of UC having also the abilityto taper
steroid treatment.
Extract of myrrh, dry extract of chamomile owers and coee
charcoal
It is well known that theherbal mixture of myrrh, dry
extract of chamomile owers and coee charcoal has anti-
inammatory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. ere was no signicant
dierence in the relapse rate between the two groups (45%
in the mesalazine group and 53% in theherbal group). No
signicant dierences were also shown in relapse-free time,
endoscopy and fecal biomarkers [20]. eherbalpreparation
was well tolerated and showed a good safety prole.
Table3 shows the results of clinical trials with plant products
of patients with UC 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. ese studies are subsequently
analyzed.
Active CD
Chios mustic gum (Pistacia lentiscus-Anacardiaceae)
Pistacia lentiscus var Chia belongs to the family of Pistacia.
is tree is unique in the world because it produces a special
resin (mastic gum). e 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 identied.
In a relevant study, the eectiveness of mastic on the clinical
course and plasma inammatory 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 signicantly

Herbal therapy of IBD 215
Annals of Gastroenterology 28
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 signicantly 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 signicant 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.
e 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 rst 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. Aer 8weeks, there was almost complete
clinical remission in 65% patients as compared to none in the
placebo group. is remission persisted until the end of the
observation period. It was also noticed that wormwood had a
steroid sparing eect and a positive eect 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. Aer 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]. e 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. Dierences in the chemical composition
of Cannabis varieties may produce dierent eects in
Table 3 Clinical trials with plant products in patients with ulcerative colitis in remission
Authors/
year
CAM No of patients Comparisons Treatment
duration
Remission on
CAM (%)
Remission on
placebo or
active drug (%)
Conclusion
Langhorst
etal, 2013
Herbal
combination of
myrrh, dry extract
of chamomile
owers and coee
charcoal
96 Mesalazine 12 months 25/47 (53) 22/49 (45)
(P=0.540)
Ecacy non-inferior to
mesalazine
Hanai
etal, 2006
Curcumin 89 Placebo 6 months 95 79 Promising and safe for
maintaining remission
in quiescent UC
Hanai
etal, 2004
Germinated
barley foodstu
(GBF) 20 g of
GBF daily
59 patients
Controls (n=37)
GBF (n=22)
Control group:
Conventional
therapy alone
for 12 months
12 months Signicantly better
CAI values in the
GBF group at 3, 6,
and 12 months
Compared
with the values
in the control
group
GBF appeared to be
eective and safe as a
maintenance therapy
to taper steroids and
prolong remission in UC
Kanauchi
etal, 2003
Germinated
barley foodstu
(GBF)
21 No placebo
arm
6 months Signicant decrease
in clinical activity
index compared
with control group
(P<0.05)
No placebo arm GBFmay have a place in
long-term management
of UC
Fernandez-
Banares
etal, 1999
Plantago ovata
seeds
105 Mesalazine 12 months 60 65 Similarly eective to
mesalazine. Side eects:
Constipation, abdominal
bloating
Greeneld
etal, 1993 Oenothera biennis 43
Evening
primrose oil &
olive oil
6 months – –
Evening primrose oil
could oer some benet
in patients with UC
CAM, complementary or alternative medicine; CD, Crohn’s disease; UC, ulcerative colitis; GBF, germinated barley foodstuff

216 A. Triantafyllidi et al
Annals of Gastroenterology 28
humans. e marijuana plant cannabis is known to improve
inammatory processes, while experimental evidence suggests
that the endogenous cannabinoid system inhibits colonic
inammation, 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 aer cannabis use in 30patients (26males) with CD was
investigated. Of the 30 patients, 21 signicantly improved
aer treatment while the need for other medication was
signicantly reduced. Fieen 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 aer the patients’
informed consent, would play a signicant role in the adoption
of this kind of treatment. It is, however, necessary to accurately
conrm the safety and eectiveness 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 aect the immune system
in dierent 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. e 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-inammatory,
immune modulating, antiproliferative and antiapoptotic).
In a study exploring the potential benet of Tripterygium
wilfordii, 20patients with active CD received tablets containing
T2 for 12weeks. CDAI was signicantly reduced during the
rst 8weeks, while endoscopic improvement was noticed aer
12weeks. e inammatory 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.
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
ecacy 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 dierences in the two
groups concerning the remission rates were noticed. Regarding
safety, no disadvantages of taking the drug compared to placebo
were observed [29]. is trial conrmed the good tolerability of
Boswelan, although there were no signicant dierences 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 rst one 45patients with CD were randomized to
receive either Tripterygium wilfordii or mesalazine. No relapse
Table 4 Clinical studies of plant treatment of patients with active Crohn’s disease
Author/year CAM Number
of patients
Comparison Duration Remission with CAM
(%)
Remission with
control agent (%)
Conclusion
Gerhardt etal,
2001
Boswellia serrata
extract H15
102 Mesalazine - 36% 31% Better results compared
to mesalazine
Kaliora et al,
2007
Mastic gum 10 Healthy
people
4 weeks Signicant reduction of
CDAI and of plasma pro-
inammatory cytokines
Not applied Eective and safe
herbal
Ren et al,
2007
Tripterygium
wilfordii
20 Placebo 12 weeks – – Eective for the
treatment of mild or
moderately active CD
Omer et al,
2007
Artemisia
absinthium
40 Placebo 10 weeks 65% 0% e available data seem
to be promising
Krebs et al,
2010
Artemisia
absinthium
20 Placebo 6 weeks 80% 20% Promising results
Naali et al,
2011 Cannabis 30 No 3 months
to 9years 70% - Positive eect on
disease activity
CDAI, Crohn’s disease activity index; CAM, complementary or alternative medicine; CD, Crohn’s disease

Herbal therapy of IBD 217
Annals of Gastroenterology 28
was noticed three months aer operation. Again in 6 and
12 months aer the operation the clinical relapse rate did
not dier in the two groups (18% vs. 22% and 32% vs. 39%,
respectively). No signicant dierences were observed in
the rate of endoscopic recurrence aer 12months (46% vs.
61%) [30].
In the second study, 39patients with CD were randomized
two weeks aer enterectomy to receive either Tripterygium
wilfordii (n=21) or sulfasalazine (n=18). Clinical recurrence
was noticed in 6% in the Tripterygium w ilfordii 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]. e 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 eective, 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.
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
e 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 benecial eects. 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 eective 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 eective 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. e
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. is 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 eects 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, antiinammatory, and immunoreguratory
properties. For example curcumin has antioxidant, anti-
inammatory, anticarcinogenic, hypocholesterolemic,
antibacterial, wound-healing, antispasmodic, anticoagulant,
Table 5 Clinical studies of plant treatment of patients with Crohn’s disease in remission
Authors/year CAM No of
patients
Comparisons Treatment
duration
Remission on
CAM (%)
Remission on placebo
or active drug (%)
Conclusion
Tao et al,
2009
Tripterygium wilfordii
(post-op CD)
45 Mesalazine 6 months
12 months
82% (6months)
68% (12months)
78% (6months)
61%(12months)
Eective and safe
Liao et al,
2009
Tripterygium wilfordii
(post-op CD)
39 Sulfasalazine – 94% 75% Eective and safe
Holtmeier et al,
2010
Boswellia serrata extract
(Boswelan, PS0201Bo)
108 Placebo 52 weeks 60% 55% Good tolerability.
Superiority versus
placebo remission is not
demonstrated
Ren et al,
2013
Tripterygium wilfordii
(post-op CD) 39 Mesala zine 52 weeks 79% 53%
Eective, superior to oral
5-ASA, for preventing
clinical and endoscopic
recurrence in post-op CD
CD, Crohn’s disease

218 A. Triantafyllidi et al
Annals of Gastroenterology 28
antitumor and hepatoprotective activities [36]. Boswellia
serrata has signicant 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]. e
extracts of wormwood (Artemisia absinthium) could reduce
TNF-α and other proinammatory 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 microoral
distribution [18,39].
However, we must bear in mind that the results obtained
from in vitro studies of an herbal preparation are not equally
eective in vivo. is 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 eects of the described
herbal and plants are shown in Table6.
Safety of herbal treatment
Most of the published trials showed no side eects. In fact,
the number and type of side eects were similar to those of
placebo or mesalazine. is is quite important in patients with
previous operations or patients who experienced signicant
side eects being on conventional treatment.
Curcumin and mastic gum probably represent the safest
herbals. Curcumin is well tolerated without any serious
toxicity and side eects. Several clinical studies have conrmed
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 eects related to
mastic gum consumption even aer long-term use has been
described.
Again, we must bear in mind that herbal therapy, in general,
could carry risks and produce side eects 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 eects 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 eect 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 suering 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 eects reported so
far are mentioned in Table7.
Table 6 Cellular, molecular and systemic eectsof described plant
and herbal preparations
Herbal and plant Cellular, molecular and systemic eects
Boswellia serrata
(Boswellic acid)
Selective inhibition of 5-lipoxygenase
Anti-inammatory eects
Direct inhibition of intestinal motility
Reduction of chemically induced edema and
inammation in the intestine in rodents
Tormentil extracts Antioxidative properties
Curcumin Decreased activity
Interferon-γ
Mitogen-activated protein kinase
IL-1, IL-4, IL-5, IL-6, IL-12
Tumor necrosis factor-α
Myeloperoxidase
Lipid peroxidase activity
Ιnducible nitric oxide synthase
Cyclooxygenase-2
Toll-like receptor- 4
Nuclear factor-κB
Binds to thioredoxin reductase and
irreversibly changes its activity
Increased activity
IL-10, IL-4,
Prostaglandin E2
Germinated
barley foodstu
(GBF)
Increases luminal butyrate production by
modulating the microoral distribution
Prebiotic action
High water holding capacity
Oenothera biennis e mature seeds contain 7-10%γ-linolenic
acid (essential fatty acid)
Plantago ovata Anti-inammatory and anti-oxidative
properties
Inhibits protein kinase C
Down-regulates the expression of
intercellular adhesion molecule-1
Inhibits the inammation produced from
5-hydroxy-6,8,11,14-eicosatetraenoic acid
and leukotriene B4
Anthocyanins Antioxidative eects
Anti-inammatory eects
Xilei San Anti-inammatory eects
Aloe vera In vitro inhibition of prostaglandin E2 and
IL-8 secretion
Triticum aestivum Antioxidant properties
Mastic gum Anti-inammatory
Antioxidant
IL, interleukin

Herbal therapy of IBD 219
Annals of Gastroenterology 28
Concluding remarks
e available data concerning the administration of extracts
derived from plants and herbals give the gastroenterologist the
excuse to explain to our patients the benets 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 nancial gain
would be much lower compared to other kinds of treatment. Both
international scientic societies and government organizations
should take seriously the locally available opportunities of drug
development by nancially 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 eective
and cheap treatment method [43]. Doctors must become more
tolerant and open-minded about the benets of AM. Finally, there
is a need for more essential representation of AM in under-and
postgraduate medical education.
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Table 7 Safety of the main herbal and plants used in inammatory bowel disease treatment
Herbal and plant Side eects Safety
Fufangkushen colon-coated
capsule (FCC)
Mild or moderate degree of nausea, fatigue, abdominal pain and
distension, anal pain, upper respiratory tract infection, dyspepsia, fever.
Similar in active substance and mesalazine [15.9% vs. 12.5]
Satisfactory
Boswellia serrata Boswellia serratais rich in guggalsterones, that increase the thyroid
function, leading to weight loss
Satisfactory
Tormentil extracts Mild upper abdominal discomfort
Incidence of side eects: 38%
No discontinuation of the medication was needed
Satisfactory
Safe up to 3000 mg/d
Wheat grass juice No serious side eects were reported Excellent
Safe as a single or adjuvant
treatment of active distal UC
Germinated barley foodstu (GBF) No side eects related to GBF were observed Excellent
Oenothera biennis Safety has not been evaluated in pregnant or nursing women Satisfactory
Plantago ovata Hypersensitivity, aer inhaled or ingested psyllium
Temporary gas and/or bloating
Satisfactory
Anthocyanins No serious adverse events have been described Satisfactory
Xilei San Well tolerated topically without safety concerns Satisfactory
Jian Pi Pian (Wan) Safely used with few adverse eects Satisfactory
Andrographis Headache, fatigue, rash, bitter/metallic taste, diarrhea, pruritus, and
decreased sex. Anaphylactic reaction in an HIV-positive patient
Moderate
Triticum aestivumL e grain could cause poisoning in stock, though no toxic substance
has been found
Wheat can absorb toxic concentrations of selenium. However,
“selenium” wheat rarely causes poisoning
Moderate
Mastic gum No side eects have been reported Excellent
Satisfactory: Side effects not different from an established active drug, Moderate: Larger number of side effects requiring close follow up during treatment,
Excellent:No difference from placebo, UC, ulcerative colitis

220 A. Triantafyllidi et al
Annals of Gastroenterology 28
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