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Nom original: Curcuma.pdfTitre: The clinical efficacy of curcumin-containing nutraceuticals_ An overview of systematic reviewsAuteur: Ester Pagano

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Pharmacological Research 134 (2018) 79–91

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

The clinical efficacy of curcumin-containing nutraceuticals: An overview of
systematic reviews


Ester Pagano1, Barbara Romano1, Angelo A. Izzo , Francesca Borrelli

T



Department of Pharmacy, School of Medicine and Surgery, University of Napes Federico II, Via D. Montesano 49, 80132 Naples, Italy

A R T I C LE I N FO

A B S T R A C T

Keywords:
Curcumin
Curcuminoids
Turmeric
Systematic review
Meta-analysis
Nutraceuticals

Background: The clinical efficacy of curcumin-containing nutraceuticals (e.g. turmeric preparations, curcumin,
curcuminoids) for a range of conditions has been assessed by several systematic reviews, in some instances with
contradictory conclusions. Our aim was to provide an up-to-date and rigorous synthesis of these data and to
evaluate the quality of the available systematic reviews.
Methods: Electronic searches were conducted (up to December 2017) to locate all systematic reviews (SRs)
related to the use of curcumin-containing nutraceuticals for any condition. The quality of the retrieved SRs was
assessed by using AMSTAR an OQAQ tolls.
Results: Twenty-two SRs met our inclusion criteria. Overall, four SRs were of high quality using the AMSTAR
scale, whereas twelve SRs achieved an high quality classification according to the OQAQ score. There is some
evidence that curcumin-containing nutraceuticals can exert systemic antioxidant actions (1 SR) and may be
effective i) in inflammatory conditions such as arthritis-related diseases and inflammatory bowel disease (12
SRs), ii) in reducing lipid levels and cardiovascular risk factors (5 SRs) as well as iii) in skin diseases (1 SR).
Cautious preliminary positive results were reported for depressive disorders (3 SRs), while no efficacy was
observed in Alzheimer's disease patients (1 SR). Curcumin-containing nutraceuticals appear to be safe, as assessed by the adverse events reported in twelve SRs.
Conclusions: Based on the currently available SRs, the efficacy of curcumin-containing nutraceuticals has been
demonstrated for several conditions; however, due to the poor quality of the primary trials and the low-tomoderate level of some SRs, there is still some uncertainty.

1. Introduction
Curcuma longa L = Curcuma domestica Val. is a perennial herb of the
ginger family (Zingiberaceae) native to India and other regions of
Southeast Asia and now cultivated in tropical and subtropical regions
around the world [1,2]. Preparations derived from the rhizome of the
plant, referred as turmeric, have been used in traditional Indian medicine to treat different diseases such as gastrointestinal and hepatic
ailments, skin diseases, infections and gynaecological problems [3–5].
The active ingredients contained in the rhizome are the curcuminoids,
i.e. a mixture of hydrophobic polyphenolic compounds consisting of
curcumin (chemically known as diferuloylmethane) and two related
compounds that are dimethoxy curcumin and bisdemethoxycurcumin
[2]. The most widely studied among the curcuminoids is curcumin, as
demonstrated by more than 9000 citations in the literature [3]. This

agent exerts a number of pharmacological actions of potential therapeutic interest [5–7] and it is extensively marketed worldwide as a
nutraceutical in various forms and preparations. The total sales of
curcumin-containing dietary supplements in the US Mainstream MultiOutlet Channel amounted to $22,057,946 in the 2016, with an increase
of 85.5% compared to 2015 [8].
The clinical efficacy of curcumin-containing nutraceuticals (CCNs)
for any indication has been assessed by a large number of clinical trials.
Starting from its first clinical trial published in the Lancet in 1937,
approximately 1200 clinical trials, involving more than 6000 human
participants, have been carried out with curcumin [3] and a number of
systematic reviews (SRs) and meta-analyses (MAs) have been recently
published. However, to date no studies have reviewed and evaluated
the evidence generated from these SRs as well as their methodological
quality. In view of this, this overview is aimed at summarizing and

Abbreviations: AMSTAR, A Measurement Tool to Assess Systematic Reviews; CCNs, curcumin-containing nutraceuticals; OQAQ, overview quality assessment questionnaire; MAs, metaanalyses; SRs, systematic reviews

Corresponding authors.
E-mail addresses: aaizzo@unina.it (A.A. Izzo), franborr@unina.it (F. Borrelli).
1
These two Authors are listed alphabetically, but equally contributed to this work.
https://doi.org/10.1016/j.phrs.2018.06.007
Received 30 April 2018; Received in revised form 29 May 2018; Accepted 7 June 2018

Available online 08 June 2018
1043-6618/ © 2018 Elsevier Ltd. All rights reserved.

Pharmacological Research 134 (2018) 79–91

E. Pagano et al.

studies [13]. Any disagreements on scores was sorted out by discussion
until a consensus was reached.
The AMSTAR checklist comprises 11 questions (focused on different
aspects of the scientific quality of a systematic review (SR), such as a
comprehensive literature search strategy, duplicate study selection and
data extraction, assessment and reporting of the clinical trials methodological quality, pooling data), each of one can have four possible
responses: yes”, “no”, “can’t answer” or “not applicable” [9,12]. Only
the answer “yes” receives a positive score (1 point), while the other
responses score 0 point [14]. Therefore, for each SR, the total score can
range from 0 (none of the answers is yes) to 11 (all the answers are yes);
a score ranging from 8 to 11 corresponds to a high-quality SR, 4–7
corresponds to a medium quality, and 3 or less corresponds to a poorquality SR [14]. Details and specifications on each AMSTAR item are
reported in the supplementary material (see Box 1S)
The OQAQ checklist comprises 10 questions, the first nine of which
evaluated several aspects of the scientific quality of a SR, such as search
and selection strategies, quality assessment, pooling data and conclusion [10,11]. Each of the nine questions can have three possible responses: yes”, “no” or “can’t tell/partially”. Only the answer “yes” receives a positive score (1 point for questions 1–4 and 9; 0.5 points for
questions 5–8), while the answer “no” or “can’t tell/partially” scored 0
points [15]. The tenth question is an overall assessment of the SR
quality and derives from the preceding nine items score. The OQAQ
score can range from 0 to 7. Specifically, score from 0 to less than 2: SR
extensively flawed (poor-quality SR); score in the range from 2 to less
than 4, SR with major flaw (poor-quality SR); score from 4 to less than
6: minor flaw (medium quality SR); score in the range 6-7: SR minimally flawed (high-quality SR) [15]. Details and specifications of each
OQAQ item are reported in the supplementary material (see Box 2S).

critically appraising all SRs and MAs that evaluated the clinical efficacy
of CCNs (e.g. curcumin, curcuminoids and turmeric extracts) for any
condition. We have robustly evaluated the methodological and reporting quality of the retrieved studies by using two complementary
quality assessment tools, i.e. “A Measurement Tool to Assess Systematic
Reviews” (AMSTAR) [9] and “Overview Quality Assessment Questionnaire” (OQAQ) [10,11].
2. Methods
2.1. Search strategy
A literature search was performed by using the following electronic
databases: Web of Science (v.5.29 which includes Pubmed/MEDLINE,
SciELO Citation Index, KCI-Korean Journal Database and Russian
Science Citation Index databases), Google Scholar, Scopus and
Cochrane Library (from their respective inception to December 2017).
Search strategy was established using the term curcum followed by the
wild-card term “*” (i.e. curcum*, thus including the terms curcumin,
curcuminoids, Curcuma) OR turmeric AND “systematic review” OR
“meta-analysis” OR “clinical trials”. No language restriction was used in
the literature search. Two researchers (EP and BR) independently
scanned the literature to identify the eligible systematic reviews, and
any discrepancies in the selection process were resolved through discussion with the other two Authors (AAI and FB). The reference lists of
included SRs were perused for possible additional articles. Finally, an
additional search was carried out on the main search engines to identify
relevant reviews: Google, Yahoo, Bing and Ask.com. The grey literature
was not searched.
2.2. Inclusion and exclusion criteria

3. Results

Studies were eligible if they met all the following inclusion criteria:
(i) the articles were SRs and/or MAs; (ii) the terms turmeric, curcuma,
curcumin, curcuminoids, Curcuma longa, or Curcuma domestica were
reported in the title or abstract; (iii) the articles evaluated the effect of
turmeric or its active ingredients (curcumin and related curcuminoids)
on any type of diseases or on blood parameters in healthy or ill subjects;
(iv) the articles reported the methods used to perform the SRs; (iv) the
articles were published as full papers;
Studies were excluded if the articles were narrative reviews. In
addition, SRs were excluded if i) there was no clear distinction between
clinical and preclinical studies analyses; ii) methods were not reported
or iii) they were not specifically focused on CCNs, but instead CCNs
were included in a more wide context related to the efficacy of nutraceuticals/dietary supplements for a specific disease.

3.1. Literature search
The study selection process is shown in Fig. 1. Our search strategy
identified 1023 potentially relevant articles evaluating the effect of
CCNs [i.e., curcumin, curcuminoids, turmeric (Curcuma) extracts, see
Box 3S for the description of the commercially-available products] for
any indication. After removal of duplicates, 812 papers remained. Once
screened (title and abstract), 26 papers were identified as potentially
eligible and full-texts were read by the two reviewers who performed
the final selection [16–41]. After full text analysis 4 articles [16–19]
were excluded for different reasons (Fig. 1). Hence, 22 SRs (including
15 MA) were included in this overview [20–41].

2.3. Data extraction
3.2. Characteristics of included systematic reviews
Two reviewers (EP and BR) independently extracted the data from
the selected studies, and any disagreement was resolved by discussion
with the other two Authors (AAI and FB). Data were extracted using
predefined criteria and exclusively from the SRs and not from the primary study reports. The following data were extracted: first author’s
name and publication year, treatment, type of disease, outcomes,
number and design of the trials, number of participants, duration of the
treatment, quality of the included studies and limitation of the included
studies/systematic review, conclusions of the SRs, adverse events and
overall scores of the AMSTAR and OQAQ tools.

The twenty-two included SRs were published between 2003 and
2017. One SR [20] published in 2017 in electronic form (i.e. as epub)
was subsequently published in hard copy form in 2018. According to
the corresponding Author affiliation, the retrieved SRs derived from
eleven countries (Iran 9, USA 3, Australia 2, and one each from the
following countries: Brazil, Indonesia, China, Singapore, UK, South
Korea, Iraq, Italy). All the retrieved SRs were published in English in
peer-reviewed Journals. Only one of the included SRs was a Cochrane
Review [41]. Table 1 reports the detailed characteristics of the retrieved SRs, including treatment, condition, main outcomes considered,
specific information on the primary trials (i.e., number of trials for each
SR, design, participants and duration of the treatment), quality and
limitation of the included studied, meta-analyses (if carried out), conclusions, adverse events (if reported) and the AMSTAR and OQAQ
scores.

2.4. Methodological quality assessment of the included SRs
Two reviewers (AAI and FB) independently assessed SRs methodological quality by using the AMSTAR [9] and the OQAQ [10,11] tools,
which have been reported to be highly reliable [12]. AMSTAR2 tool
was not used because we did not include SRs analysing observational
80

Pharmacological Research 134 (2018) 79–91

E. Pagano et al.

Fig. 1. Flow chart of included systematic review.

reported by twenty-one SRs [20,34,35,37–41]; the scientific quality of
the included trials was assessed and documented in twenty-one SRs
[20,38–40]; the scientific quality of the included studies in formulating
the conclusion was considered in nine SRs [20,22,26,28–30,34,40,41];
a
meta-analysis
was
performed
in
fifteen
SRs
[20,21,23–25,27,29,31–38] and the likelihood of publication bias was
assessed in twelve SRs [20,21,27,29,31–37,40]. Finally, seventeen SRs
[20,21,23,25,29,30,33,38–40] out of the twenty-two SRs explicitly reported information concerning the absence of any conflict of interest.
Table 3 reports the overall OQAQ score for each SR and the total
score for each single item of the checklist. The median OQAQ score was
6 (range: 3.5–7). Twelve SRs were classified as “high quality SR”
[20,23–26,29,33–35,37,38,40], eight as “medium quality SR”
[21,22,27,30–32,36,39] and the remaining two were classified as “poor
quality SR” [28,41]. The poor quality of the two SRs was mainly due to
biases in the selectin of the studies and to the lack of inclusion criteria,
of “a priori” methods of validity assessment of the included studies and
of a meta-analysis [28,41]. The analysis of the individual OQAQ
checklist items pointed out that the main biases were due i) to a lack of

3.3. Quality assessment of the SRs
The methodological quality of included SRs, assessed by AMSTAR
and OQAQ tools, varied widely (Table 1). Table 2 reports the overall
AMSTAR score for each SR included in our overview and the total score
for each single item of the AMSTAR checklist. The median AMSTAR
score was 5.5, ranging from 3 to 9. Only four of the twenty-two retrieved SRs were classified as “high quality SR” [20,26,34,40]; sixteen
SRs were of “medium quality” [21,23–25,27–33,35–39], and two were
classified as “low quality SR” [22,41]. A careful analysis of each of the
eleven items of the AMSTAR checklist highlighted as follows: a clear a
priori design was performed in four SRs [20,26,34,40]; the studies were
selected and the data were extracted at least by two independent reviews in four SRs [20,23,34,40]; a comprehensive literature search was
performed in twelve SRs [20,24–26,28,33–35,37–40]; the publication
status as inclusion criteria investigating the scientific and the grey literature was considered in two SRs only [26,29]; a list of both the included and excluded studies was provided by six SRs
[23,25,26,37,38,40]; the characteristic of the included studies was
81

82
1. High quality (n = 4),
moderate quality (n = 3)
(Cochrane risk of bias).
2. Interpretation of
outcomes, bias related to
unpublished studies or
grey literature, Asian
subjects only, some data
were obtained indirectly

MS, T2D

Seven
RCTs (six
with
placebo,
five
doubleblind)
649
4 weeks-6
months

Turmeric extract
equivalent to 6001890 mg/die
curcuminoids 2-2.4 g;
Curcumin nanomicelles
(80 mg/die);
Turmeric powder (22.4 g/die);
Amorphous dispersion
curcumin (70 mg/die
curcuminoids

Qin,
2017
[23]
Republic of
China

1. NR
2. NR

Three
RCT
179
1-12
months

Blood
lipid
levels
(TC, LDLC, HDL-C,
TG)

UCDAI,
CAI

1. Unclear or low risk of
bias in 11/12 trials
(Cochrane risk of bias).
2. Short duration of the
trials, unformulated
curcuminoids with low
bioavailability,
heterogeneity with
respect to the target
population and
characteristics

Twenty
RCT
1427
7 days-6
months

TG, HDLC, LDL-C,
TC

Various diseases
(acute coronary
syndrome, elderly
subjects, T2D,
chronic
obstructive
pulmonary
disease,
hyperlipideamina,
coronary artery
disease, MS,
NAFLD), healthy
individuals
Ulcerative colitis

Curcumin (456000 mg/die)
Curcuminoids (2941000 mg/die)
Turmeric (1.2-1.4 g/
die)

SimentalMendía,
2017
[21]
Iran

Curcumin (2-3 g die)
NCB-02 (enema, 1 per
day)

1. Low (n = 8) or high
(n = 3) risk of bias
(Cochrane risk of bias).
2. Different way to
deliver curcuminoids,
lack of subgroup analysis,
short duration of trials

Eleven
RCT
1157
4 weeks
-36 weeks

FBG,
HbA1c,
HOMA-IR

MS, high ALT
patients,
hyperlipidemia,
T2D/MS, NAFLD/
MS, Alzheimer

Turmeric (2.4-3 g/die)
Curcumin (0.07-4 g/
die)
Curcuminoids (0.31.5 g/die)

de Melo,
2018
[20]
Brazil

Simadibrata,
2017
[22]
Indonesia

1. Quality of the included
studies
2. limitations of the
included studies

Primary
trials:
Number
Design
Participant
Duration

Main
outcomes

Condition

Treatment

First author,
year, reference,
country of the
corresponding
author

Table 1
Characteristics of included systematic reviews.

“Available evidence showed that
curcumin has the potential to
induce and maintain remission in
UC patients with no serious side
effects”
“Turmeric and curcumin may
protect patients at risk of CVD
through improving serum lipid
levels”.

Not performed

Turmeric and curcumin
significantly reduced serum
LDL-C (SMD = −0.340,
C.I. − 0.530 to −0.150,
P < 0.0001) and TG (SMD =
−0.214, CI: −0.369 to −0.059,
P = 0.007) levels as compared
to those in the control group;
Turmeric and curcumin lowered
TC levels in patients with
metabolic syndrome (SMD =
−0.934, 95% CI: −1.289 to
−0.579, P < 0.0001).
Turmeric extract could be more
effective than curcumin in
reducing serum TC levels (SMD
= −0.584, 95% CI: −0.980 to
−0.188, P = 0.004);
Serum HDL-C levels were not
changed

6
6

4

3

5

5

7

9

OQAQ
score

AMSTAR
score

(continued on next page)

No
difference
between
treated and
placebo
groups
No serious
adverse
events

Generally
safe and
well
tolerated

NR

“Supplementation of isolated
curcumin or combined
curcuminoids were both effective
in lowering the FBG
concentrations of individuals with
some degree of dysglycemia, but
not in non-diabetic individuals.
Isolated curcumin lead to
significant decreases of the HbA1c
compared to placebo”.
“Curcuminoid therapy
significantly reduces plasma TG
and increases HDL-C levels”

Turmeric/curcuminoids
supplementation decreased FBG
(WMD -8.88 mg/dL, CI: -5.04,
-2.72, P = 0.005) and HbA1c
(WMD -0.54, CI: -1.09, -0.002,
P = 0.049)
No significant changes in
HOMA–IR (WMD -1.26, CI
-3.71, -1.19), P = 0.31).
Turmeric/curcuminoids
significantly reduced TG (WMD:
-21.36 mg/dL,% CI: -32.18,
-10.53, P < 0.001), and
increased HDL-C levels (WMD:
1.42 mg/dL, CI: 0.03, 2.81,
P = 0.046);
No significant changes in LDL-C
(WMD: -5.82 mg/dL, CI: -15.80,
4.16, P = 0.253) and TC (WMD:
-9.57 mg/dL, CI: -20.89, 1.75,
P = 0.098).

Adverse
events

Conclusion

Meta-analysis

E. Pagano et al.

Pharmacological Research 134 (2018) 79–91

83

Atkin,
2017
[27]
Iran

Gaffey, 2017
[26]
Australia

Onakpoya,
2017
[25]
UK

Curcuminoids (2501000 mg/die)

Curcuma domestica
extract (1.5-2 g/die)
Curcuma longa extract
(1 g/die)
Curcumin (600 mg/
die)
Theracurmin®
(1800 mg/die)
Curcuminoids (1.5 g/
die)
Curcuminoids extract
(0.5 g/die)
Meriva® (2 g/die
corresponding 400 mg
curcumin)
Curcuminoids
(1500 mg/die)
Theracurmin®
(corresponding to
1800 mg/die)
Curcumin (1000 mg/
die as BCM)

T2D, MS,
depression,
obesity

Musculoskeletar
pain

Knee osteoarthritis

Major depression

Curcumin with
piperine (0.5-1 g die);
BCM-95® (1 g/die);
Curcumin (1 g/die)

Ng,

2017
[24]
Singapore

Condition

Treatment

First author,
year, reference,
country of the
corresponding
author

Table 1 (continued)

Thirteen
RCT
1101
4-32 weeks

Five
RCT, with
placebo
(three
doubleblind)
345
4 weeks-6
months

Plasma
leptin

Seven
RCT (five
with
placebo,
two with
ibuprofen)
797
4-16 weeks

Six
RCT (four
doubleblind)
377
4-8 weeks

Primary
trials:
Number
Design
Participant
Duration

VAS,
WOMAC,
LPFI

Various
depression
measurement
scales
(CGI-S,
HAM-D17,
HAM-D,
HADS,
MADRS,
BDI, BAI,
STAI,
DSM-IV,
IDS-SR30)
WOMAC,
VAS,
JKOM,
LPFI, QoL

Main
outcomes

1. Strong (n = 5),
moderate (n = 6) or
weak (n = 2) quality (JBI
MAStARI)
2. Variability in the
quality of studies, small
sample sizes, short
duration of interventions,
a gender-bias towards
females, absence of longterm data extraction and
small number of relevant
studies.
1.Median Jadad score: 2
2. Small sample size,
small treatment duration

1. Low risk of bias
(n = 3), Unclear risk of
bias (n = 4) (Cochrane
risk of bias).
2. Bias related to
unpublished studies;
small number of RCTs, no
dose-effect, only Asian
patients

1. Low risk of bias
(n = 4), high risk of bias
(n = 2) (Cochrane risk of
bias); Median Jadad
score: 4.5;
2. Small number of
studies, only English,
short duration, only
patients with unipolar
depression

1. Quality of the included
studies
2. limitations of the
included studies

4

5

6

8

6

6

7

4

OQAQ
score

AMSTAR
score

(continued on next page)

NR

“Curcumin supplementation is
associated with a decrease in
leptin
levels that may be regarded as a
potential mechanism for the
metabolic effects of curcumin”
Curcuminoids significantly
decreased plasma leptin
concentrations (SMD: -0.69, CI:
-1.16, -0.23, P = 0.003)

No serious
adverse
events

“Curcuminoids may have some
beneficial effects on knee pain and
quality of life in patients with
knee OA. However, they are less
effective at relieving pain
compared with ibuprofen”

Minor
adverse
events

No adverse
event in any
trials

“Curcumin appears to be safe,
well-tolerated, and efficacious
among depressed patients”

“There is insufficient evidence to
recommend that curcuminoids be
considered for relieving pain and
improving function in
musculoskeletal pain conditions”

Adverse
events

Conclusion

Not performed

Curcuminoids significantly
reduced knee pain (VAS, SMD:
-3.45; CI: -5.52 to -1.38;
P = 0.001) and improved
quality of life (Lequesne painfunction index: MD: -2.69;
95% CI: -3.48 to -1.90;
P < 0.00001) compared to
placebo.

Curcumin preparations
significantly reduced Hamilton
rating scales for depression
(SMD -0.344, C.I. -0.558 to
-0.129; P = 0 .002).

Meta-analysis

E. Pagano et al.

Pharmacological Research 134 (2018) 79–91

Vaughn,
2016
[30]
USA

Skin diseases
(acne, alopecia,
atopic dermatitis,
facial photoaging,
oral lichen planus,
pruritus, psoriasis,
radiodermatitis,
vitiligo)

Joint Arthritis

Depression

Curcumin Forte
Balance (500 mg/daily,
containing 330 mg of
curcumin plus piperine
and ellagic acid);
BCM-95® (0.5-1 g/day
containing 440-880 mg
curcuminoids);
C3 complex® (1 g/
die, > 95%
curcuminoids);
C3 complex® (1 g/
die, > 95%
curcuminoids) with
piperine
Curcuminoids 1 g/die
(Curcuma domestica
extract)
Curcumin 0-5-1 g/die
TurmacinTM (1 g/die
turmeric extract)
Meriva® (500 mg/die)
C3®complex (1.5 g/die)
Theracurmin®
(corresponding to
1080 mg/die
curcuminoids)
Curcumin extract
(1.5 g/die containing
75-85% curcuminoids
Curcuma extract,
curcumin,
Oral ingestion (9 trials)
Topical application (8
trials) or both (1 trial)

Lopresti,
2017
[28]
Australia

Daily,
2016
[29]
South Kora

Condition

Treatment

First author,
year, reference,
country of the
corresponding
author

Table 1 (continued)

Eight
RCT (4
with
placebo)
937
4 weeks-4
months

Eighteen
12 RCT, 6
uncontrolled
and/or
unrandomized,
1019
4 weeks-6
months

Various

Seven
6 RCT (five
doubleblind), 1
CCT
528
4-12 weeks

Primary
trials:
Number
Design
Participant
Duration

WOMAC,
PVAS

CGI,
MADRS,
HDRS,
HAM-D17,
CGI-S,
IDS-SR30,
STAI,
BDI-II,
BDI,
BAI,HADS

Main
outcomes

84
1. Median Jadad score:5
(n = 11 trials)
2. Small sample size, poor
research design, studies
in combinations, English
Database

1. High (n = 4 or
moderate (n = 4) quality
(Cochrane risk of bias).
2. Small sample size,
various turmeric
preparation, use of
different end-points

1. Median Jadad score: 4
2. Limited number of
studies, flawed protocol
design

1. Quality of the included
studies
2. limitations of the
included studies

Not performed

Curcumin preparations reduced
PVAS (MD: -2.04, CI -2.85,
-1.24, P < 0 .00001) and
WOMAC (MD: -15.36, CI: -26.9,
-3.77, P = .009) compared to
placebo.

Not performed

Meta-analysis

NR

Safe at
doses not
exceeding
1200 mg/
day for up
to 4
months.

NR

“Although not uniformly
consistent, the bulk of evidence is
positive pro curcumin as an
effective antidepressant and
anxiolytic agent for people with
major depressive disorders"

“These RCTs provide scientific
evidence that supports the
efficacy of turmeric extract (about
1000 mg/day of curcumin) in the
treatment of arthritis"

“There is early evidence that
turmeric/curcumin products and
supplements, both oral and
topical, may provide therapeutic
benefits for skin health”

5

4

6

7

3.5

5

OQAQ
score

AMSTAR
score

(continued on next page)

Adverse
events

Conclusion

E. Pagano et al.

Pharmacological Research 134 (2018) 79–91

85

Al-Karawi, 2016
[34]
Iraq

Major depressive
disorders

Various diseases
(obesity, T2D
nephropathy,
major depression,
knee
osteoarthritis, MS
and sulfur
mustard-exposed
veterans)
Various diseases
(laparoscopic
intervention,
rheumatoid
arthritis, breast
cancer, knee
osteoarthritis,
heavy exercise,
pancreatitis)

Curcumin
300-1500 mg/die

Sahebkar,
2016
[32]
Iran

Curcuminoids (0.5-6 g/
die alone or in
combination with
piperine)
Curcuma domestica
extract (standardized
to 75-85%
curcuminoids) 1.5-2 g/
die
Phytosomal curcumin
(1 g/die corresponding
to 200 mg/die
curcuminoids)
Curcumin 0.5-1 g

Osteoatrhritis,
oral lichen planus,
T2D, sulfur
mustard
intoxication,
chronic pruritic
skin lesions, MS

Curcumin
(0.2- 6 g/die)

Derosa,
2016
[31]
Iran

Sahebkar,
2016
[33]
Iran

Condition

Treatment

First author,
year, reference,
country of the
corresponding
author

Table 1 (continued)

Various
depression
measurement
scales
(CGI-S,
HAM-D17,
MADRS,
BDI, BAI,
DSM-IV,
IDS-SR30)
Six
4 RCT, 2
CCT
377
4-8 weeks

1. Strong quality (n = 5),
moderate quality (n = 1)
(Cochrane risk of bias).
2.Small number, limited
dosage, short duration,
different measurement
scales, language
restriction

1. Median Jadad score: 3
2. Small sample size,
publication bias,
heterogeneity in terms
painful conditions,
different doses and
treatment duration

1. Low (n = 2) or unclear
(n = 6) risk of bias;
(Cochrane risk of bias).
2. Small sample size,
assessment of TNF-α was
not the primary objective,
different diseases

Eight
RCT
549
4 weeks-3
months

Circulating levels
of TNF-α

Eight
RCT
606
4 days-8
weeks

1. High (n = 1), low
(n = 2) or unclear
(n = 6) risk of bias;
(Cochrane risk of bias).
2. Study heterogeneity,
study design, duration,
short follow-up duration

Nine
8 RCT, 1
CCT
609
2 weeks-8
months

Circulating IL-6
levels

VAS, pain
severity

1. Quality of the included
studies
2. limitations of the
included studies

Primary
trials:
Number
Design
Participant
Duration

Main
outcomes

Curcumin significantly reduced
depressive symptoms (SMD=0.34; CI =-0.56, -0.13;
P = 0.002).
Subgroup analyses showed that
curcumin had the highest effect
when given to middle-aged
patients (SMD = 0.36; 95%
CI = 0.59; 0.13; P = 0.002), for
longer duration of
administration (SMD = 0.40;
95% CI = 0.64, 0.16;
P = 0.001), and at higher doses
(SMD = 0.36; 95%CI = 0.59,
0.13; P = 0.002).

7

9

6

6

5

4

5

4

OQAQ
score

AMSTAR
score

(continued on next page)

Non serious
adverse
effects

“There is supporting evidence that
curcumin administration reduces
depressive symptoms in patients
with major depression”

NR

“Our analysis indicated a
promising impact of curcumin on
circulating TNF-α concentration.
However, lowering of TNF-α
concentrations was independent
of curcumin dose and duration of
treatment"

Safe and
well
tolerated

NR

"Significant effect of curcumin in
lowering circulating IL-6
concentrations. This effect
appears to be more evident in
patients with higher degrees of
systemic inflammation"

Curcumin reduced IL-6
concentrations (WMD:
−0.60 pg/mL, CI: −1.06,
−0.14, P = 0.011).
There was a significant
association between the IL-6lowering activity of curcumin
and baseline IL-6 concentration
(slope: −0.51; CI: −0.80,
−0.23; P = 0.005).
No significant association
between IL-6 lowering effects
and curcumin dose or duration.
Curcumin significantly reduced
TNF-α (WMD: −4.69 pg/mL,CI:
−7.10, −2.28, P < 0.001);
No significant association
between the circulating TNF-α
lowering effects of curcumin
with dose or treatment duration
(slope: 0.197; CI: −1.73, 2.12;
P = 0.841).
Curcuminoids significantly
reduce pain (SMD: 20.57, CI:
21.11 to 20.03, P = 0.04).
No significant association
between the effect with dose or
duration
“Curcuminoids supplements may
be a safe and effective strategy to
improve pain severity”

Adverse
events

Conclusion

Meta-analysis

E. Pagano et al.

Pharmacological Research 134 (2018) 79–91

Various diseases
(Alzheimer’s
disease, acute
coronary
syndrome, T2D,
obese
dyslipidemic
patients) healthy
subjects
Various diseases
(dyslipidemia,
patients suffering
from chronic
complication due
to sulfur mustard,
oral lichen planus,
osteoarthritis,
patients with
undergoing
coronary artery
bypass grafting),
healthy
individuals

C3 complex® (1-6 g
curcumin/die)
Purified curcuminoids
(4 g/die)
Longvida® (80 mg
curcumin/die)
Meriva®
(200 mg curcumin/die)

Sahebkar, 2014
[38]
Iran

Not reported

Curcuminoids 806000 mg/die

Panahi,
2015
[36]
Iran

Curcuminoids
(45-6000 mg/die)
Curcuma longa extract
(300 mg curcuminoids/
die)

Various diseases
(obese subjects,
solid tumors, MS,
patients suffering
from chronic
pulmonary
complication due
to sulfur mustard
exposure, knee
osteoarthritis) and
healthy
individuals

Curcumin 80-1500 mg/
die

Sahebkar,
2015
[35]
Iran

Sahebkar,
2014
[37]
Iran

Condition

Treatment

First author,
year, reference,
country of the
corresponding
author

Table 1 (continued)

86
Circulating levels
of CRP

1. Low (n = 1), unclear
(n = 3) and high (n = 1)
risk of bias; (Cochrane
risk of bias).
2. Small sample size,
heterogeneity

1. Median Jadad score:
3.5
2. Small sample size,
heterogeneity,
unpublished results bias,
short duration, different
patients included, CRP
not being the primary
outcome

Six
5 RCT, 1
CCT
342
6 days- 3
months

1. NR
2. NR

Eight
RCT
562
2 weeks-12
weeks

Five
RCT
223
1 week-6
months

1. Median Jadad score: 3
2. Small sample size,
short follow-up (up to 8
weeks) heterogeneity
in population
characteristics, study
design, and curcumin
dose.

6
RCT
396
4-8 weeks

Serum
SOD
activity,
GSH
concentration,
catalase
activity
and lipid
peroxides
levels

Circulating CRP
and MDA
levels and
serum
activity of
SOD
Serum
lipid
parameters

1. Quality of the included
studies
2. limitations of the
included studies

Primary
trials:
Number
Design
Participant
Duration

Main
outcomes

NR

“Supplementation with
curcuminoids may reduce
circulating CRP levels. This effect
appears to depend on the
bioavailability of curcuminoids
preparations and also duration of
supplementation”

6

6

6

7

4

4

7

6

OQAQ
score

AMSTAR
score

(continued on next page)

NR

NR
"Curcuminoids could be regarded
as natural, safe and effective CRPlowering agents"

“Curcumin supplementation has
apparently no effect
on serum total cholesterol, LDL-C,
triglycerides and HDL-C levels
when considering heterogeneous
populations”

NR

"This meta-analysis
showed a significant effect of
curcuminoids in elevating serum
SOD and catalase activities,
GSH concentrations, and
reduction of serum lipid
peroxides"

Curcumin significantly
increased serum SOD activities
(WMD = 1.15 U/mL, 95%
CI = 0.49; 1.82, P = 0.0007),
GSH concentrations
(WMD = 5.39 g/mL,
95%CI = 1.17; 9.60, P = 0.01),
catalase activity (WMD = 51.78
U/mL, 95% CI: 15.71;87.85,
P = 0.005) and reduced serum
lipid peroxides
(WMD = −6.35 nmol/mL,
95%CI: −11.06; −1.64,
p = 0.008).
Curcuminoids significantly
reduced CRP concentrations
(WMD: -2.20 mg/L; CI -3.96,
-0.44, P = 0.01).

No significant effect on any of
the lipid parameters.
Total cholesterol (MD: 8.97 mg/
dL, CI -4.56,22.51, P = 0.19)
HDL-C (MD: 16.15 mg/dL, CI
-4.43, 36.74, P = 012)
HDL-C (MD: - 0.59 mg/dL, CI
-1.66,0.49, P = 0.28)
Triglycerides (MD:-1.29 mg/dL,
CI -9.05,6.48, P = 0.75).
Curcuminoids significantly
reduced circulating CRP levels
(WMD: -6.44 mg/L; CI: _-10.77,
-2.11; P = 0.004).

Adverse
events

Conclusion

Meta-analysis

E. Pagano et al.

Pharmacological Research 134 (2018) 79–91

87
Rheumatoid
arthritis,
postsurgical
patients, chronic
anterior uveitis,
idiopathic
inflammatory
orbital tumors

Various

Four
1 RCT, 2
CCT, 1 case
series
121
5 days-22
months

1. NR
2. NR

1. Low (n = 2) and high
(n = 1) risk of bias
Cochrane
2. Small sample size,
curcumin poor
bioavailability, short
follow-up period
1. Low risk of bias
(Cochrane risk of bias).
2. NR

Three
2 RCT, 1
case study
75
24 weeks-1
year
1
RCT
89
6 months
treatment
plus 6
months
follow up

1. Quality of the included
studies
2. limitations of the
included studies

Primary
trials:
Number
Design
Participant
Duration

"Curcumin may be an effective
and safe therapy in maintenance
of remission in ulcerative
colitis when given with standard
treatments."

Relapse a 6 months: there was a
non-significant trend towards
benefit in the curcumin
group: (curcumin 4%; placebo
18%)
RR 0.24, CI: 0.05, 1.09;
P = 0.06).
Relapse at 12 months: there was
no statistically significant
difference between groups: (RR
0.70, CI: 0.35, 1.40; P = 0.31).
CAI was significantly
lower in the curcumin group
compared to the placebo group
(1.0 ± 2.0 versus 2.2 ± 2.3;
MD − 1.20, CI: −2.14, −0.26).
EI was significantly lower in the
curcumin group than in the
placebo group (0.8 ± 0.6
versus 1.6 ± 1.6; MD − 0.80,
CI: −1.33, − 0.27).
Not performed

“Curcumin has demonstrated
antinflammatory activity”

No
difference
between
curcumin
and placebo

“There is insufficient evidence to
suggest the use of curcumin in
dementia patients”

Not performed

No
significant
side effects

Adverse
events were
reported
but without
distinction
between
groups

Adverse
events

Conclusion

Meta-analysis

3.5

2

6.5

9

5

4

OQAQ
score

AMSTAR
score

ADAS-Cog, Alzheimer's Disease Assessment Scale-cognitive subscale; ALT, alanine aminotransferase; BAI, Beck Anxiety Inventory; AMSTAR, A Measurement Tool to Assess Systematic Reviews; BDI, Beck Depression
Inventory II; CAI, Colitis Activity Index; CCT, Controlled clinical trial; CGI-S, Clinical Global Impression Severity Scale; CI, 95% Confidence Interval; CRP, C-Reactive Protein; DSM-IV, Diagnostic and Statistical Manual of
Mental Disorders, fourth edition; EI, Endoscopic Index: FBG, Fasting Blood Glucose; GSH, Glutathione HADS, Hospital Anxiety and Depression Scale; HAM-D17, Hamilton Depression Rating Scale, 17-item version; HbA1c,
Glycated Haemoglobin; HDL-C, High Density Lipoprotein Cholesterol; HOMA-IR, Homeostasis model assessment index for insulin resistance; IDS-SR30, Inventory of Depressive Symptomatology self-rated version; IL-6,
Interleukin-6; JKOM, Japanese Knee Osteoarthritis Measure; LDL-C, Low density Lipoprotein Cholesterol; LPFI, Lequesne Pain-Function Index; MADRS, Montgomery–Asberg Depression Rating Scale; MMSE, Mini-Mental
State Examination; MS, Metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; NPI-Q, Neuropsychiatric Inventory Questionnaire; NR, Not Reported; OQAQ; Overview Quality Assessment Questionnaire; PVAS,
pain visual analogue score; QoL, Quality of Life; RCT, Randomized Controlled Trial; SMD, Standardized Mean Difference; SOD, Superoxide Dismutase; STAI, Spielberger State-Trait Anxiety Inventory; T2D, type 2
diabetes; TC, Total Cholesterol; TG, Triglycerides; TNF-α, Tumor necrosis factor-α; VAS, Visual Assessment Scale; UCDAI, Ulcerative Colitis Disease Activity Index; WMD, Weighted Mean Difference; WOMAC, Western
Ontario and McMaster Universities Osteoarthritis Index.

Curcumin 11251200 mg/die

Ulcerative colitis

Curcumin 2 g/die

Garg, 2014
[40]
USA

Chainani-Wu,
2003
[41]
USA

MMSE,
NPI-Q,
ADASCog

Alzheimer’s
dementia

Curcumin
(0.1 g-4 g/die)
C3 Complex®
(2-4 g/die)

Brondino,
2014
[39]
Italy

Maintenance of
remission
in
ulcerative
colitis
(evaluated at 6
and 12
months).
CAI
(evaluated at 6
months)
EI
(evaluated at 6
months)

Main
outcomes

Condition

Treatment

First author,
year, reference,
country of the
corresponding
author

Table 1 (continued)

E. Pagano et al.

Pharmacological Research 134 (2018) 79–91

Pharmacological Research 134 (2018) 79–91

E. Pagano et al.

Table 2
Methodological quality of the identified SRs assessed by the AMSTAR tool.
First author,
year, reference

de Melo, 2018 [20],
Simental-Mendia, 2017 [21],
Simadibrata, 2017 [22],
Qin, 2017 [23],
Ng, 2017 [24],
Onakpoya, 2017 [25],
Gaffey, 2017 [26],
Atkin, 2017 [27],
Lopresti, 2017 [28],
Daily, 2016 [29],
Vaughn, 2016 [30],
Derosa, 2016 [31],
Sahebkar, 2016 [32],
Sahebkar, 2016 [33],
Al-Karawi, 2016 [34],
Sahebkar, 2015 [35],
Panahi, 2015 [36],
Sahebkar, 2014 [37],
Sahebkar, 2014 [38],
Brondino, 2014 [39],
Garg, 2014 [40],
Chainani-Wu, 2003 [41],
Total

Items
1

2

3

4

5

6

7

8

9

10

11

1





1







1





1

4

1


1










1





1

4

1



1
1
1

1




1
1
1

1
1
1
1

12







1


1












2




1

1
1










1
1

1

6

1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1

1
1
1
1
1
21

1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1

21

1

1



1

1
1
1



1





1
1
9

1
1

1
1
1

1

1

1
1
1
1
1
1
1
1



15

1
1





1

1

1
1
1
1
1
1
1


1

12

1
1

1

1
1
1
1
1
1


1
1
1
1
1
1
1
1

17

Overall score

Review’s quality

9
5
3
6
4
6
8
5
5
7
4
4
4
6
9
6
4
7
6
4
9
2

High
Medium
Poor
Medium
Medium
Medium
High
Medium
Medium
Medium
Medium
Medium
Medium
Medium
High
Medium
Medium
Medium
Medium
Medium
High
Poor

AMSTAR, A Measurement Tool to Assess Systematic Reviews.

effect on circulating fasting blood glucose (1 SR) [20], oxidative stress
parameters (1 SR) [35], lipid levels (3 SRs) [21,23,37], leptin levels (1
SR) [27], interleukin-6 levels (1SR) [31], TNF-α levels (1 SR) [32] and
C-reactive protein (2 SRs) [36,38].

a comprehensive search to retrieve the studies and ii) to an inappropriate selection process (e.g. not carried out by two or more authors).

3.4. Effect of curcumin-containing nutraceuticals (CCNs)
4. Discussion
The included SRs investigated the effect of CCNs for a number of
conditions that are inflammatory states and pain (7 SRs)
[22,25,26,29,33,40,41], skin diseases (1 SR) [30], depression (3 SRs)
[24,28,34] and dementia (1 SR) [39]. Some other SRs investigated the

Due to lack of rigorous regulation, nutraceutical-based products
may reach the market without compelling evidence of efficacy [7,42].
In such context, overview of SRs, by bringing together evidence from

Table 3
Methodological quality of the identified SRs assessed by using the OQAQ tool.
First author,
year, reference

de Melo, 2018 [20],
Simental-Mendia, 2017 [21],
Simadibrata, 2017 [22],
Qin, 2017 [23],
Ng, 2017 [24],
Onakpoya, 2017 [25],
Gaffey, 2017 [26],
Atkin, 2017 [27],
Lopresti, 2017 [28],
Daily, 2016 [29],
Vaughn, 2016 [30],
Derosa, 2016 [31],
Sahebkar, 2016 [32],
Sahebkar, 2016 [33],
Al-Karawi, 2016 [34],
Sahebkar, 2015 [35],
Panahi, 2015 [36],
Sahebkar, 2014 [37],
Sahebkar, 2014 [38],
Brondino, 2014 [39],
Garg, 2014 [40],
Chainani-Wu, 2003 [41],
Total

Items

Review’s quality

1

2

3

4

5

6

7

8

9

10

1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
22

1



1
1
1

1




1
1
1

1
1
1
1
1
13

1
1
1
1
1
1
1
1

1
1
1
1
1
1
1
1
1
1
1
1

20

1


1
1

1


1
1



1
1




1

9

0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5

0.5
0.5
0.5
0.5
0.5
0.5
0.5

0.5
0.5
0.5
0.5

9.5

0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5

0.5
0.5
0.5
0.5
0.5
10.5

0.5
0.5

0.5
0.5
0.5

0.5

0.5

0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5

0.5

8

0.5
0.5

0.5
0.5
0.5

0.5

0.5

0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5



7.5

1
1
1
1
1
1
1

1
1
1
1
1
1
1
1
1
1
1
1
1
1
21

7
5
4
6
7
6
6
4
3.5
6
5
5
5
6
7
7
4
6
6
5
6.5
3.5

OQAQ; Overview Quality Assessment Questionnaire.
88

High
Medium
Medium
High
High
High
High
Medium
Poor
High
Medium
Medium
Medium
High
High
High
Medium
High
High
Medium
High
Poor

Pharmacological Research 134 (2018) 79–91

E. Pagano et al.

quiescent ulcerative colitis when given as adjunctive therapy along
with mesalamine or sulfasalazine [40]. The intestinal anti-inflammatory effect of curcumin was further supported by a more recent
poor quality (AMSTAR) or medium quality (AQAQ) SR [22], which
included two RCTs on curcumin efficacy to induce remission and one
(already included in the above mentioned Cochrane review) for remission maintenance in ulcerative colitis. Results showed that curcumin was more effective than placebo in all three retrieved RCTs [22].
Consistently, another overview reported that curcumin reduced Chron’s
diseases symptoms and inflammatory markers in intestinal cells as well
as in preclinical and clinical studies [16].
In summary, based on the published SRs, there is some evidence
that CCNs are effective in patients with arthritis-related diseases and
may also reduce molecules or biomarkers indicative of systemic inflammation. Additionally, preliminary evidence suggests that curcumin
has the potential to induce and maintain remission in ulcerative colitis
patients.

multiple SRs and MAs in a rigorous fashion, may provide reliable information on the clinical efficacy of specific nutraceuticals [43]. Our
overview identified twenty-two SRs (including fifteen MAs) on the
clinical efficacy of CCNs. On average, the review quality of the retrieved
SRs was medium (according to AMSTAR) or high (according to OQAQ).
The vast majority of the SRs (16 out of 22) have been published in the
2016–2017 years, indicating that the scientific interest for curcumin
has grown considerably in recent years. Indications covered by SRs
include inflammation and pain [22,25,26,29,31–33,35,36,38,40,41],
metabolic diseases [20,21,23,27,37], skin diseases [30] and CNS disorders [24,28,34,39].
4.1. Inflammation and pain
Anti-inflammatory and analgesic effects of turmeric have been
known for centuries and studies over the last three decades have consistently demonstrated that curcumin is a key ingredient of the antiinflammatory and analgesic actions of turmeric preparations [44].
Curcumin mediates its anti-inflammatory action through multiple mechanisms, including downregulation of inflammatory transcription
factors, cytokines, redox status, protein kinases and translocation of NFκB into the nucleus [45,46]. An early low-quality SR [41] demonstrated
that curcumin was safe and displayed anti-inflammatory activity in
humans. More recently, the potential analgesic and anti-inflammatory
effects of CCNs have been investigated in four SRs. Two medium-tohigh quality SRs in patients with knee osteoarthritis (n = 797 patients)
[25] or joint arthritis (knee osteoarthritis and rheumatoid arthritis,
n = 937 patients) [29] provide evidence that CCNs may have beneficial
effects. The quality of the primary trials was considered to be at low or
unclear risk of bias in both SRs. Similarly, a further medium-to high
quality SR with MA of data from eight RCTs (median Jadad score: 3) in
patients with a number of inflammatory/painful conditions, indicated a
significant effect of curcuminoids supplementation in reducing pain
severity [33]. By contrast, an high-quality SR performed by Gaffey and
coworkers [26] concluded that there is insufficient evidence to recommend curcuminoids for moderating pain and improving function in
musculoskeletal pain condition. The discrepancy could be explained
considering that Gaffey and coworkers [26], differently from the previous SRs [25,29,33] specifically evaluated the effect of curcuminoids
on musculoskeletal pain.
Cytokines are small proteins that play an important role in immune
competent cell signalling and are now recognized as important mediators of inflammatory pain [47]. On the other hand, preclinically
curcumin has been shown to be an orally-active blocker of TNF-α and
other cytokines [48]. Two medium-quality SRs, by the same research
group, have investigated the effect of curcumin on the circulating levels
of interleukin-6 [31] and TNF-α [32], two cytokines involved in the
acute inflammatory phase [49]. MAs of RCTs, most of them with “unclear risk of bias” showed that curcumin lowered circulating levels of
both interleukin-6 [31]and TNF-α [32]. In the case of interleukin-6, the
effect was more evident in patients with higher degrees of systemic
inflammation [31]. Additionally, two independent meta-analyses, one
of medium quality [36] based on eight RCTs (quality of trials not assessed) and the other of medium-to-high quality [38] based on 5 RCTs
and one CCT (Jadad median score: 3.5) revealed that supplementation
with curcuminoids lowered circulating levels of C-reactive protein
[36,38], a routinely used biomarker of systemic inflammation. Collectively, these SRs lend additional support to the systemic anti-inflammatory effect of CCNs.
Curcumin has been shown to exert beneficial effects on experimental models of colitis [50]. The precise mode of action is elusive, but
there is copious evidence demonstrating its effects on the NF-κB
pathway and p38 MAPK in the gut mucosa [51]. A Cochrane review,
scored to be of “high quality” according to both AMSTAR and OQAQ
tools, which included one RCT (at low risk of bias, n = 89 patients)
concluded that curcumin is effective for maintenance of remission in

4.2. Metabolic diseases
Curcumin interacts with a number of molecular targets that are
involved in the pathogenesis of metabolic syndrome [52] and CCNs
have been clinically evaluated in patients with metabolic diseases, including diabetes, obesity and hyperlipidemia. Two SRs with MAs, one
of medium-(AMSTAR)-to-high-(OQAQ)-quality [23] including seven
RCTs (four at low risk of bias and three at unclear risk of bias) for a total
of 649 patients with metabolic syndrome or type-2 diabetes, and another of medium-quality, including 20 RCTs (with unclear or low risk of
bias in 11 out of 12 trials) with 1427 patients suffering of various
diseases [21] revealed that CCNs improved serum lipid levels. Specifically, CCNs, namely turmeric extract, curcumin nanomicelles, turmeric
powder and amorphous dispersion curcumin i) reduced serum LDL-C
and triglycerides levels compared to placebo [23] and ii) reduced
plasma triglycerides levels and increased HDL-C levels [21]. A beneficial effect on total cholesterol levels was observed only in a more
homogeneous group of patients, i.e. patients with hyperglycaemia and
metabolic syndrome [23]. These results are not in agreement with a
previous medium-(AMSTAR)-to-high-(AQAQ)-quality meta-analysis of
five RCTs (three at unclear risk of bias, one at low risk of bias and
another one at high risk of bias) who failed to detect a significant lipidlowering effect of curcumin [37]. The discrepancy could be due to
different reasons, including study selection (crossover design not included in one SR [23]), the use of different curcumin formulations such
as unformulated curcumin, which is considered to have low bioavailability and, importantly, the analysis of new trials in the two more
recent SRs reporting positive results [21,23]. Finally, it is worth mentioning that, as highlighted above, CCNs lower circulating C-reactive
protein [36,38], which is now considered as a novel biomarker for
cardiovascular risk prediction [53].
In summary, although not all analyses yielded similar results, there
is some promising – but not compelling - evidence that CCNs may have
beneficial effects in metabolic and cardiovascular risk patients, as
highlighted by their ability to reduced serum lipid levels and circulating
C-reactive protein. The reduction in plasma leptin concentration, observed in a very recently-published medium-quality MA [27] might be
viewed as a potential mechanism for the metabolic effects of CCNs.
Future well-designed and long-term trials, by using specific curcumin
formulations, are warranted to make definitive conclusions.
4.3. Skin diseases
Curcumin and curcuminoids have a recognized potential for skin
diseases, due to their anti-inflammatory, antimicrobial, immunomodulatory, antioxidant, and wound healing activities [54,55]. A
medium-quality SR examining the effects of topical and oral turmeric
and curcumin on skin diseases identified 18 trials (12 RCTs, 6
89

Pharmacological Research 134 (2018) 79–91

E. Pagano et al.

formulations. Finally, vi) even if we tried to be meticulous in our search
strategy, the possibility that we missed relevant studies cannot be completely ruled out. Collectively, these drawbacks limit the conclusiveness of
our findings.

uncontrolled or unrandomized trials) [30]. Skin diseases included alopecia, atopic dermatitis (eczema), acne, androgenetic facial photoageing, oral liken planus, pruritus, psoriasis, vitiligo and radiodermatitis. Ten studies showed statistically superiority of CCNs over the
control. The Authors concluded that there is some clinical evidence that
oral or topical turmeric/curcumin formulations may have a beneficial
effect on skin health [30]. However, the poor research design and the
small sample size of the included trials limit the interpretation of the
results. It should be noted that the use of turmeric/curcumin preparations may be limited by the yellow-orange colour of curcumin, which
may stain the skin.

4.6. Adverse effects
The safety of CCNs has been extensively explored [63]. Turmeric extracts and curcumin are nonmutagenic and nongenotoxic, are safe in
pregnant animals and have been shown to not display any major toxic effects when given to rodents [63]. For example, oral curcumin for 70 days, at
doses up to 10,000 ppm was found to be not toxic in rats [64]. According to
animal studies, standardized powder and extract of turmeric and curcumin
are safe for human use even at high doses (1.5 g/day curcumin) and for
periods up to 6 months [63]. Concerning our overview, twelve SRs reported
adverse effects, which were classified as mild in general, similar to placebo.
The most frequent adverse events included abdominal pain, nausea and
dyspepsia.
Collectively, CCNs appear to be safe. However long-term data, studies in infants/adolescents or pregnant women and more trials evaluating nanoformulations are needed to fully substantiate the safety of
this nutraceutical.

4.4. Central nervous system disorders (depression and dementia)
Curcumin interacts with several neurotransmitter systems and intracellular signalling pathways involved in mood regulation [56].
Two recent SRs with MAs, one of medium quality, including six RCTs
(four trials at low risk of bias and two at high risk of bias), for a total of 377
patients with unipolar depression [24] and another one of high-quality including 4 RCTs and two CCTs (five trials at low risk of bias and one at
unclear risk of bias) for a total of 342 patients with major depressive disorders [34], agreed that curcumin preparations, administered for a period of
4–8 weeks may be effective in depressed patients. Cautious positive results
were also provided by a further medium quality (AMSTAR) or poor quality
(AQAQ) SR without MA [28]. The Authors retrieved seven human trials (six
RCT and one CCT, median Jadad score: 4) on depression (severity not
specified), three of which investigating the efficacy of curcumin as a standalone antidepressant and four as an adjunct to antidepressant therapy [28].
Clearly the conclusions about the efficacy of curcumin for the treatment of
depression must be tempered by the limited number of studies and patients
and by the flawed protocol designs used in some of the retrieved trials.
Curcumin exerts antioxidant, anti-inflammatory, anti-amyloidogenic
and neurotrophic effects, suggesting a potential to treat or prevent physiopathological states associated with neurodegeneration [56,57]. Brondino
and colleagues retrieved three clinical studies (two double-blind RCTs at
low risk of bias and one case open label study at high risk of bias) related to
the possible beneficial effect of curcumin in patients with Alzheimer’s disease [39]. Curcumin was used as an adjunct treatment to other therapies
which included Gingko biloba preparations, acetylcholinesterase inhibitors
plus memantine and donepezil. Collectively, trials yielded negative or inconclusive results. The SR was scored as medium-quality according to both
AMSTAR and AQAQ tools.

5. Conclusions
In conclusion, our overview based on 22 SRs (including 15 MAs) suggests that CCNs might be useful for a number of conditions including skin
diseases (e.g. alpecia, atopic dermatitis, acne, androgenetic facial photoageing, psoriasis), arthritis-related diseases (an effect associated to reduction
of molecules or biomarkers suggestive of systemic inflammation), metabolic
diseases (due to the CCNs ability to lower circulating lipids, C-reactive
protein and leptin) and possibly, although in a very preliminary fashion,
depressive disorders and ulcerative colitis. By contrast, there is no evidence
that curcumin is effective in Alzheimer’s disease. There are no specific safety
concerns related to the use of CCNs.
Such collectively promising results should be interpreted cautiously due
to the high risk of bias in many primary trials, the low-moderate level of
some analyses, as assessed by AMSTAR and OQAQ tools, and the different
preparations used in clinical trials, an important point in the light of the
consideration that curcumin bioavailability, which is generally low, can be
enhanced by specific formulations or in association with inhibitors of metabolism. Consequently, some uncertainty remains about the therapeutic
value of CCNs. Further rigorously-designed large sample-size RCTs are
needed to fully exploit the potential of CCNs for any indication.

4.5. Limitations

Appendix A. Supplementary data

Our overview has a number of important limitations: i) as a general
notion, overviews are always susceptible to the interpretive, conceptual, and
reporting biases of previous reviewers [58]; ii) by evaluating SRs rather than
primary trials, important information is lost; iii) even though most of these
SRs have been classified as “high quality SRs", the methodological quality of
some primary trials might be unsatisfactory; frequent shortcomings included
small sample size, publication bias, study heterogeneity and high or unclear
risk of bias; iv) our overview does not comprise clinical trials which were
previously not included in SRs or MAs. Thus, some potentially-important
clinical applications could have been not mentioned here. Also, our overview does not include SRs/MAs not specifically focused on CCNs. For example, CCNs have been included in SRs related to the use of dietary supplements or nutraceuticals in the treatment of tendinopathies [59], drugsinduced nephrotoxicity [60] or fibroids treatment [61]; iv) in many trials
and SRs there is not a clear distinction between the treatment, which ranged
from curcumin and curcuminoids to turmeric extracts. Importantly, one of
the main problems associated to curcumin use is its low bioavailability,
which can be enhanced by the use of adjuvants, liposomal curcumin, curcumin nanoparticles, curcumin phospholipid complexes and association
with inhibitors of metabolism [3,62]. Therefore, some negative results [e.g.
26,37,39] might be due to the use of poor-bioavailable curcumin

Supplementary material related to this article can be found, in the
online version, at doi: https://doi.org/10.1016/j.phrs.2018.06.007.
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