Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial

Abstract

Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC).
Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up.
Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P=.040). Recurrence rates evaluated on the basis of intention to treat showed significant difference between curcumin and placebo (P=.049). Furthermore, curcumin improved both CAI (P=.038) and EI (P=.0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed.
Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.

Full text

Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized,
Multicenter, Double-Blind, Placebo-Controlled Trial
HIROYUKI HANAI,*
,‡
TAKAYUKI IIDA,
‡
KEN TAKEUCHI,
‡
FUMITOSHI WATANABE,
§
YASUHIKO MARUYAMA,
§
AKIRA ANDOH,
储
TOMOYUKI TSUJIKAWA,
储
YOSIHIHIDE FUJIYAMA,
储
KEIICHI MITSUYAMA,
¶
MICHIO SATA,
¶
MASAMI YAMADA,
#
YASUSHI IWAOKA,
#
KAZUNARI KANKE,** HIDEYUKI HIRAISHI,** KAZUHISA HIRAYAMA,
††
HAJIME ARAI,
‡‡
SHIGEHITO YOSHII,
‡‡
MASATO UCHIJIMA,
§§
TOSHI NAGATA,
§§
and YUKIO KOIDE
§§
*Department of Endoscopic and Photodynamic Medicine and
§§
Department of Microbiology and Immunology, Hamamatsu University School of Medicine,
Hamamatsu;
‡
Center for Gastroenterology, Hamamatsu South Hospital, Hamamatsu;
§
Department of Gastroenterology, Fujieda Municipal General Hospital,
Shizuoka;
储
Department of Internal Medicine, Shiga University of Medical Science, Shiga;
¶
Second Department of Medicine, Kurume University School of Medicine,
Kurume;
#
Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu; **Department of Gastroenterology, Dokkyo University School of Medicine,
Tochigi;
††
Department of Surgery, Hamamatsu Social Insurance Hospital, Hamamatsu; and
‡‡
Hamamatsu Mikatahara Seirei Hospital, Hamamatsu, Japan
Background & Aims: Curcumin is a biologically active
phytochemical substance present in turmeric and has pharma-
cologic actions that might benefit patients with ulcerative co-
litis (UC). The aim in this trial was to assess the efficacy of
curcumin as maintenance therapy in patients with quiescent
ulcerative colitis (UC). Methods: Eighty-nine patients with
quiescent UC were recruited for this randomized, double-blind,
multicenter trial of curcumin in the prevention of relapse.
Forty-five patients received curcumin, 1g after breakfast and 1g
after the evening meal, plus sulfasalazine (SZ) or mesalamine,
and 44 patients received placebo plus SZ or mesalamine for 6
months. Clinical activity index (CAI) and endoscopic index (EI)
were determined at entry, every 2 months (CAI), at the conclu-
sion of 6-month trial, and at the end of 6-month follow-up.
Results: Seven patients were protocol violators. Of 43 patients
who received curcumin, 2 relapsed during 6 months of therapy
(4.65%), whereas 8 of 39 patients (20.51%) in the placebo group
relapsed (P⫽.040). Recurrence rates evaluated on the basis of
intention to treat showed significant difference between curcumin
and placebo (P⫽.049). Furthermore, curcumin improved both
CAI (P⫽.038) and EI (P⫽.0001), thus suppressing the morbidity
associated with UC. A 6-month follow-up was done during which
patients in both groups were on SZ or mesalamine. Eight addi-
tional patients in the curcumin group and 6 patients in the
placebo group relapsed. Conclusions: Curcumin seems to be
a promising and safe medication for maintaining remission in
patients with quiescent UC. Further studies on curcumin
should strengthen our findings.
Ulcerative colitis (UC) is a debilitating, chronic, relapsing-
remitting IBD that afflicts millions of individuals
throughout the world and produces symptoms that impair
quality of life and ability to function.
1
Although factors like
smoking cessation,
2
use of nonsteroidal anti-inflammatory
drugs,
3
and stress
4
are known to provoke an exacerbation,
clinical relapses are often unpredictable.
Currently, several drugs including sulfasalazine (SZ), me-
salamine, corticosteroids, immunomodulators, and remicade
are used to treat patients with active IBD.
5–12
However, these
medications are associated with side effects that add to the
disease complications when used either to induce remission or
to prevent a recurrence.
9–15
Furthermore, given that the major-
ity of patients with UC (approximately 70%) have a clinical
course that is either relapsing-remitting or chronic continuous,
there is a need for novel safe medications to maintain remission
in patients with UC in whom the disease has reverted to a
quiescent state.
Curcumin is a natural substance present in turmeric, the
spice that gives food an exotic yellow color. Curcumin seems to
have a broad spectrum of pharmacologic actions including
antitumor, anti-inflammatory, and antioxidant effects.
16–20
The pleiotropic effects of curcumin are attributable in part
to the inhibition of the transcriptional nuclear factor–
␬
B
(NF-
␬
B).
21–23
In line with this background, recently we demon-
strated that treatment with curcumin can prevent murine ex-
perimental colitis by inhibiting N
˜F-
␬
B activation and CD4⫹
T-cell infiltration into the colonic mucosa.
24
This study aimed
to assess the efficacy of curcumin as a maintenance therapy in
patients with quiescent UC.
Patients and Methods
Patients
Between April 2004–July 2005, 8 centers in Japan en-
rolled a total of 89 patients. The study protocol was reviewed
and approved by the Committees on Ethics of clinical trials
involving human subjects at each institution, and the trial was
conducted in accord with the Declaration of Helsinki. Inclusion
criteria were (1) patient had a diagnosis of UC as confirmed by
radiologic, endoscopic, or histologic criteria that are established
by the Research Committee of Inflammatory Bowel Disease,
the Japan Ministry of Health; (2) age between 13–65 years;
(3) patient’s UC had a clinical activity index (CAI) ⱕ4, stable for
the previous 4 weeks; (4) patient had achieved remission with a
corticosteroid ⱖ20 mg/day prednisolone or an alternative med-
ication and had successfully ceased steroid therapy; and
(5) patient had a hemoglobin of ⱖ10 g/dL. Exclusion criteria
were (1) patient was receiving an immunomodulator like aza-
Abbreviations used in this paper: CAI, clinical activity index; EI,
endoscopic index; MAPK, mitogen-activated protein kinase; NF-␬B,
nuclear factor-␬B; NOS, nitric oxide synthase; SZ, sulfasalazine; TNBS,
trinitrobenzene sulfonic acid; UC, ulcerative colitis.
©2006 by the AGA Institute
1542-3565/06/$32.00
doi:10.1016/j.cgh.2006.08.008
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:1502–1506

thioprine, 6-mercaptopurine, or cyclosporine; (2) patients with
severe cardiovascular diseases; (3) patients with laboratory ab-
normalities indicating anemia (hemoglobin ⬍9 g/dL), leukope-
nia, thrombocytopenia, or abnormal coagulation; (4) patients
with renal or liver disease, chronic pancreatitis, diabetes melli-
tus, or gallstone; (5) patients with infection, sepsis, or pneumo-
nia; and (6) pregnant or nursing women. Dropout criteria were
(1) patient exhibits complications during the study; (2) patient
decides to withdraw from the trial at will; and (3) patient
requires additional drug therapy that violates the inclusion
criteria. Any adverse symptom was recorded in the diary kept by
patients during the study. Laboratory investigations including a
complete blood count and blood chemistry were performed 3
times, at baseline, at 3 months, and at the end of the treatment.
Methods
This study was to be a randomized, multicenter (8
hospital institutions), double-blind, and placebo-controlled
clinical trial. Assignment to curcumin or placebo was according
to a computer-generated randomization scheme done by the
clinical pharmacist. Patients were given SZ (1.0–3.0 g/day; me-
dian, 2.0 g/day) or mesalamine (1.5–3.0 g/day; median, 2.25
g/day) plus 2 g curcumin, 1 g taken after breakfast and 1 g after
the evening meal, or placebo for 6 months (Figure 1). Patients
were then followed for an additional 6 months, during which
either SZ or mesalamine was continued. All medications except
SZ or mesalamine were discontinued 4 weeks before starting
this study. All study personnel and participants were blinded to
treatment assignment for the duration of the study. Only the
study statisticians and the data monitoring committee could
see unblinded data, but none had any contact with the study
patients. Curcumin and placebo were made to have identical
appearance (yellow), prepared by API Co, Ltd (Gifu, Japan). The
compositions of curcumin and placebo are shown in Table 1.
Clinical Assessment
CAI was measured at entry (within 2 weeks before
randomization), every 2 months, and then at the conclusion of
the clinical trial, whereas endoscopic index (EI) was determined
at entry and at the conclusion of the trial. Both CAI and EI were
according to Rachmilewitz.
25
Patients who had a CAI ⱕ4 were
considered to be in clinical remission, whereas relapse was
defined as CAI ⱖ5.
Statistical Analysis
Data are presented as the mean ⫾standard deviation
values and ranges unless indicated otherwise. For determining
statistical significance, comparisons were made by using the
Fisher exact test or the
␹
2test. Pvalue ⬍.05 was considered
significant in all statistical evaluations.
Results
Clinical Outcomes
Seven patients (2 in the curcumin group and 5 in the
placebo group) were excluded in line with patients’ wishes.
Hence, 43 patients in the curcumin group and 39 patients in
the placebo group completed the study. Study groups were
well-matched with respect to gender, age, duration of UC,
recurrences during the past 2 years, clinical course, CAI, and EI
(Table 2). Recurrent rates evaluated in all patients (intention to
treat) also showed significant differences between the curcumin
and the placebo groups (P⫽.049, Table 3). Relapses in the 2
groups during the 6-month study period together with the
Figure 1. Summary of the study design, randomization, and clinical
outcomes of the 6 months of treatment.
Table 1. Compositions of Medications (%)
Curcumin Placebo
Curcumin 50.0 Microcrystalline cellulose 25.0
Microcrystalline
cellulose
42.5 Dextrin 29.6
Malitol 7.5 Cornstarch 10.0
Malitol 35.0
FD & C Yellow No. 5 0.15
FD & C Yellow No. 6 0.04
Caramel color 0.2
Total 100 100
Table 2. Demography of Patients at Baseline
Demography Curcumin Placebo Pvalue
Male/female 23/22 26/18 .52
Age, mean (y) 45.2 ⫾15.8 39.7 ⫾14.2 .11
Range (18–75) (21–68)
Duration of UC (mo) 98.6 ⫾74.2 93.5 ⫾74.2 .77
Range (11–305) (5–336)
No. of recurrences during
past 2 y
1.6 ⫾1.2 1.5 ⫾1.0 .78
Range (0–5) (0–4)
Clinical course (cases)
First attack 5 4
Relapsing-remitting 29 28
Chronic continuousa10 8 .89
CAI before study 1.3 ⫾1.1 1.0 ⫾1.1 .23
Range (0–4) (0–4)
EI before study 1.3 ⫾0.8 1.3 ⫾1.0 .60
Range (0–3.0) (0–3.6)
Mean ⫾standard deviation values and (ranges) are presented.
aPatients with chronic continuous UC had a CAI ⱕ4 for at least 4
weeks before entry. “Chronic continuous” is commonly used in Japan
to indicate a CAI that oscillates between fully quiescent (0 –1) and
clinical remission (4) in some patients.
December 2006 CURCUMIN FOR MAINTENANCE THERAPY 1503

follow-up data are presented in Figures 1 and 2. Of the 43
patients who received curcumin, 2 patients (4.55%) relapsed
during 6 months, whereas 8 of 39 patients (20.51%) in the
placebo group relapsed (P⫽.040) (Table 4).
We also determined the mean CAI and EI values before and
after the treatment (Table 5). The mean CAI in the curcumin
group was improved from 1.3 ⫾1.1 at baseline to 1.0 ⫾2.0 at
6 months (P⫽.038). In contrast, CAI in the placebo group
showed significant deterioration; mean CAI increased from
1.0 ⫾1.1 to 2.2 ⫾2.3 (P⫽.0003). Furthermore, patients in the
curcumin group had significantly improved EI, 1.3 ⫾0.8 vs
0.8 ⫾0.6 (P⫽.0001). The EI values in the placebo group
showed no significant difference between baseline and post-
treatment.
Follow-up Observations
A 6-month follow-up was done after the end of the
6-month study period. As shown in Figure 2, 8 additional
patients in the curcumin group and 6 patients in the placebo
group relapsed during the 6-month follow-up while being on
SZ or mesalamine. There was no significant difference between
the 2 groups with respect to relapse rates during the 6-month
follow-up.
Safety Evaluation
A total of 9 mild and transient side effects in 7 of 89
patients were observed during curcumin maintenance therapy.
Some patients experienced more than 1 event. The side effects
included sensation of abdominal bulging, nausea, transient
hypertension, transient increase in the number of stools,
and elevated
␥
–guanosine triphosphate level. The elevated
␥
–guanosine triphosphate was observed in a patient who was a
regular alcohol drinker. No patient discontinued curcumin
therapy as a result of side effects, except 1 patient with hyper-
tension.
Discussion
The clinical outcomes of this double-blind, placebo-
controlled trial of curcumin therapy to sustain remission in
patients with quiescent UC might be briefly summarized as
follows: (1) 2 g/day curcumin in combination with SZ or me-
salamine had significantly better clinical efficacy in the preven-
tion of relapse compared with placebo plus SZ or mesalamine;
(2) curcumin significantly improved both CAI and EI; and
(3) curcumin was well-tolerated and was not associated with
any serious side effect.
Most currently available conventional drugs used to treat UC
are associated with unpleasant side effects. For example, nausea,
vomiting, headaches, rash, fever, hepatitis, pancreatitis, nephri-
tis, agranulocytosis, and male infertility are reported in approx-
imately 30% of patients who take SZ.
1
The sulfa moiety of the
drug is known to interfere with folic acid absorption. Even the
mesalamine derivatives that lack the sulfa moiety are associated
with fever, diarrhea, and abdominal discomfort. In contrast,
none of these side effects were observed when patients were
given curcumin. Curcumin is a diferulolymethane, a natural
plant product extracted from the root of Curcuma longa Linn.It
Table 4. Recurrence Status at 6 Months
Curcumin Placebo Pvalue
No. of patients treated 43 39
No. of patients with
recurrence
28
% with recurrence 4.65 20.51 .040
95% confidence interval 0.56–15.47 9.30–36.46
Analysis is based on the number of eligible patients who completed
the study, excluding the 7 patients who became protocol violators
during the study.
Table 3. Recurrence Rates at 6 and 12 Months Based on
Intention to Treat
Curcumin Placebo Pvalue
No. of patients randomized 45 44
No. of patients with
recurrence at 6 mo
28
% with recurrence at 6 mo 4.44 15.15 .049
95% confidence interval (%) 0.54–15.15 8.19–32.71
No. of patients with
recurrence at 12 mo
10 14
% with recurrence at 12 mo 22.2 31.8 .433
95% confidence interval (%) 11.2–37.1 18.6–47.6
Figure 2. The Kaplan-Meier curves showing the efficacy outcomes during the 6 months of therapy and 6 months of follow-up.
1504 HANAI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 12

is a common food additive popular for its pleasant mild aroma
and exotic yellow color, not likely to cause side effects. In India
and China, for centuries curcumin has been known as a medic-
inal plant. It is very likely that curcumin has several biochemical
actions that are not yet elucidated. Recently, curcumin was
reported to block the upstream of NF-
␬
B and I
␬
B kinase.
26
NF-
␬
B is suspected to promote the expression of human
IBD.
26–28
Consistent with this assertion, recently we demon-
strated that curcumin can suppress colonic inflammation in-
duced by trinitrobenzene sulfonic acid (TNBS) in a mice model
of colitis.
24
In the present study, only 2 of 43 patients treated with
curcumin in combination with SZ or mesalamine relapsed
during the 6 months of therapy, whereas 8 of 39 patients who
received placebo with SZ or mesalamine relapsed during the
same period. It is appropriate to mention that mesalamine
alone when used as maintenance therapy during a 6-month
period has an efficacy similar to that of SZ, which is equal to the
placebo group in our study.
29,30
In addition, in this study, we
added a 6-month follow-up to the 6-month treatment time
during which patients received SZ or mesalamine only. Clinical
assessment at the end of the follow-up showed no significant
difference between the 2 groups. This supported our impression
that curcumin, in fact, does suppress relapse.
The 2-g curcumin per day in this study is similar to the dose
reported to have antitumor effect.
31
However, we admit that the
dose of curcumin used in this study might not be the optimum
and the most effective regimen. This could be viewed as one
major limitation of our data. With this in mind, we believe that
future studies in larger cohorts of patients should use multiple
doses of curcumin, because a dose higher than 2 g/day might
appear superior to 2 g/day.
Aminosalicylates have been reported to be inhibitors of
NF-
␬
B.
4
However, curcumin has broader effects on the NF-
␬
B
signal transduction pathways. In addition, curcumin inhibits
mitogen-activated protein kinase (MAPK),
32
c-Fos, and nitric
oxide synthase (NOS) activity,
33
thus potentially having a
broader spectrum of anti-inflammatory effects compared with
aminosalicylates (not to mention its safety).
In our study, both the clinical and endoscopic evaluation
scores were significantly improved by curcumin therapy. Espe-
cially the endoscopic score was substantially improved com-
pared with the placebo. Nine of the curcumin-treated patients
reported some mild side effects such as abdominal bloating and
nausea. Because the patients were also receiving SZ or me-
salamine as well, we could not with certainty attribute these
complaints to curcumin. A phase I human trial with 25 subjects
using up to 8 g curcumin per day found no toxicity or serious
side effects related to curcumin.
34
Therefore, we conclude that
curcumin therapy is both effective and safe in maintaining UC
remission.
In conclusion, the results of this study indicate that the
turmeric component, curcumin, is potentially a promising med-
ication for the treatment of IBD. In the near future, we plan to
undertake a multiple-dose (including a high-dose) curcumin
trial without an aminosalicylate as maintenance therapy in
patients with quiescent UC.
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Address requests for reprints to: Yukio Koide, MD, PhD, Department
of Microbiology and Immunology, Hamamatsu University School of
Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. e-mail:
koidelb@hama-med.ac.jp; fax: 81-53-435-2335.
Supported by the Broad Medical Research Program (IBD-0069) from
The Eli and Edythe L. Broad Foundation.
1506 HANAI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 12