Received: 11 September 2017 Revised: 4 January 2018 Accepted: 17 January 2018

DOI: 10.1002/ptr.6054

REVIEW

Turmeric (Curcuma longa) and its major constituent (curcumin)

as nontoxic and safe substances: Review
Vahid Soleimani1 | Amirhossein Sahebkar2 | Hossein Hosseinzadeh3

1
School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran Curcumin is the major constituent of turmeric (Curcuma longa). Turmeric has been widely used as
2
Biotechnology Research Center, a spice in foods and for therapeutic applications such as anti‐inflammatory, antihyperlipidemic,
Pharmaceutical Technology Institute, Mashhad and antimicrobial activities. Turmeric and curcumin are nonmutagenic and nongenotoxic. Oral
University of Medical Sciences, Mashhad, Iran
use of turmeric and curcumin did not have reproductive toxicity in animals at certain doses.
3
Department of Pharmacodynamics and
Studies on human did not show toxic effects, and curcumin was safe at the dose of 6 g/day orally
Toxicology, School of Pharmacy, Mashhad
University of Medical Sciences, Mashhad, Iran for 4–7 weeks. However, some adverse effects such as gastrointestinal upsets may occur.
Correspondence Moreover, oral bioavailable formulations of curcumin were safe for human at the dose of
Hossein Hosseinzadeh, Pharmaceutical 500 mg two times in a day for 30 days, but there are still few trials and more studies are needed
Research Center, Pharmaceutical Technology specially on nanoformulations and it should be discussed in a separate article. In addition,
Institute, Mashhad University of Medical
curcumin is known as a generally recognized as safe substance. This review discusses the safety
Sciences, Mashhad, Iran.
Email: hosseinzadehh@mums.ac.ir and toxicity of turmeric and curcumin in medicine. Turmeric and curcumin are nontoxic for human
especially in oral administration. Turmeric and curcumin are also safe in animals. They are
nonmutagenic and are safe in pregnancy in animals but more studies in human are needed.

KEY W ORDS

clinical trial, Curcuma longa, curcumin, safety, toxicology, turmeric

1 | I N T RO D U CT I O N effects on tobacco smoke‐induced liver cancer (Liang et al., 2017).

Curcumin, a polyphenolic yellow substance, is the major constituent of
turmeric (Curcuma longa L from Zingiberaceae family). It comes from
the rhizome of the plant. This plant from ancient times until now has
been used for different purposes, for example, in foods and for thera-
peutic uses and widely used in India (Aggarwal, Sundaram, Malani, &
Ichikawa, 2007; Ammon & Wahl, 1991; Kunnumakkara et al., 2017),
and also, turmeric is one of the most popular dietary supplements in
the world (Andrew & Izzo, 2017). Many studies have been done on
curcumin and this substance has a variety of effects. Curcumin
reduced hyperlipidemia and insulin resistance and affects high‐density
lipoprotein functionality (Sahebkar, 2014; Ganjali et al., 2017; Jang
et al., 2008; Panahi, Ahmadi, Teymouri, Johnston, & Sahebkar, 2016).
It reduced liver fat in patients with nonalcoholic fatty liver disease
(Rahmani et al., 2016). Curcumin as anticancer agent (Allegra et al.,
2017) has good effects in head and neck squamous cell carcinoma
(Wilken, Veena, Wang, & Srivatsan, 2011), and also, it is effective in
suppressing gastric, colon, and breast cancer (Banik, Parasuraman,
Adhikary, & Othman, 2017; Khosropanah et al., 2016; Liu, Xiang, Wu,
& Wang, 2016; Tong, Wang, Sun, & Suo, 2016). It has preventive
Recently, this agent has shown antimetastatic effect (de Campos
et al., 2017; Deng, Verron, & Rohanizadeh, 2016). Curcumin also has
cytotoxic effects on tumor cells (Khosropanah et al., 2016; Liu & Chen,
2013; Syng‐Ai, Kumari, & Khar, 2004). It also has suppressive effects
on lung cancer stem cells (Zhu et al., 2017). In addition,
nanoformulations of curcumin have been used for the treatment of
cancer (Davatgaran‐Taghipour et al., 2017; Lee et al., 2014). In chemo-
therapy, curcumin has positive effects and is a chemosensitizer and
also reduces toxic and adverse effects of chemotherapeutic drugs
(Goel & Aggarwal, 2010; Rezaee, Momtazi, Monemi, & Sahebkar,
2017). In addition, curcumin has been shown radioprotective effects
on normal cells (Goel & Aggarwal, 2010; Inano & Onoda, 2002) and
protective effects against damage caused by ultraviolet B (Li et al.,
2016). Turmeric and curcumin have beneficial effects on the health
of the skin (Vaughn, Branum, & Sivamani, 2016). Curcumin has been
shown to exert anti‐inflammatory activity (Akyuz et al., 2016; Fadus,
Lau, Bikhchandani, & Lynch, 2016; Panahi et al., 2012) and can be used
for osteoarthritis (Henrotin, Priem, & Mobasheri, 2013). Topical appli-
cation of turmeric has beneficial effects in the treatment of psoriasis
(Sarafian et al., 2015). Curcumin also has antibacterial (Moghadamtousi

Phytotherapy Research. 2018;1–11. wileyonlinelibrary.com/journal/ptr Copyright © 2018 John Wiley & Sons, Ltd. 1
2 SOLEIMANI
et al., 2014; Yun & Lee, 2016), antiviral, and antifungal effects
(Moghadamtousi et al., 2014). It has antidiabetic effects (Zhang, Fu,
Gao, & Liu, 2013) and turmeric ethanolic extract (containing curcumin,
demethoxycurcumin, and bisdemethoxycurcumin) can decrease blood
glucose in mice and prevent increase in blood glucose (Kuroda et al.,
2005). Oral administration of turmeric reduced proteinuria and hema-
turia in patients with refractory lupus nephritis (Khajehdehi et al.,
2012). In obese people, curcumin showed immunomodulatory and reg-
ulatory effects on serum concentrations of interleukin (IL)10, vascular
endothelial growth factor, and IL‐1β (Ganjali et al., 2014). Curcumin
has beneficial effects on Alzheimer's disease (Mishra & Palanivelu,
2008; Ringman, Frautschy, Cole, Masterman, & Cummings, 2005) and
it was effective in treatment of major depressive disorder (Al‐Karawi,
Al Mamoori, & Tayyar, 2016; Ng, Koh, Chan, & CYX, 2017) and has
an effective role in reducing the symptoms of premenstrual syndrome
(Khayat et al., 2015). Moreover, in obese people, curcumin showed
antianxiety activity (Lao et al., 2006; Esmaily et al., 2015; Figure 1).
Curcumin has low bioavailability even at dose of 12 g/day orally in
human. At this dose, serum concentration of curcumin is 51.2 ng/ml
(Anand, Kunnumakkara, Newman, & Aggarwal, 2007; Lao et al.,
2006). However, micronized powder and liquid micellar of curcumin
increased oral bioavailability (Schiborr et al., 2014).
Toxicity of herbals is very important because of wide uses of them
and until now, many studies were done around toxicity on some plants
such as Glycyrrhiza glabra, Crocus sativus, and Berberis vulgaris (Bostan,
Mehri, & Hosseinzadeh, 2017; Nazari, Rameshrad, & Hosseinzadeh,
2017; Phua, Zosel, & Heard, 2009; Rad, Rameshrad, & Hosseinzadeh,
2017). So due to excessive uses of curcumin, this review discusses
about safety and/or toxicity of turmeric and its major constituent
curcumin in cell cultures, animals, and human subjects.
1.1 | Literature search
Web of Science and PubMed databases were used for literature search
to find relevant studies assessing the safety and toxicity of curcumin or
turmeric in animals and humans. The keywords and search terms that
were used included Curcuma longa, toxicity, safety, turmeric, curcumi-
noids, oral administration, intravenous administration, intraperitoneal
FIGURE 1 A schematic of some actions of turmeric [Colour figure can be viewed at wileyonlinelibrary.com]
ET AL.
administration, pathological effects, adverse effects, mutagenicity,
genotoxicity, cytotoxicity, reproductive toxicity, double‐blind random-
ized placebo controlled clinical trials, acute toxicity, sub‐acute, and
sub‐chronic toxicity.
2 | RESULTS
We collected 227 studies and 50 of them were selected. Included
articles assessed following subjects (some of these subjects are
discussed together jointly in one article): acute toxicity (includes eight
articles), subacute toxicity (includes one article), and subchronic
toxicity (includes five articles) studies of turmeric and its major
constituent (curcumin) and in animals since 1992 to end of 2016. We
also mentioned about toxicity of turmeric essential oil in animals as a
component of turmeric. We collected studies about turmeric and
curcumin around cytotoxicity (includes five articles), reproductive
toxicity (includes three articles), mutagenicity, genotoxicity, and chro-
mosomal aberration (includes five articles). In human studies, we col-
lected double‐blind, randomized, placebo controlled (noncrossover)
human clinical trials (includes 28 articles) since 2006 to end of 2016.
In animal (rats and mice) studies, we used various physical forms of
turmeric/curcumin such as turmeric ethanolic standardized extract,
turmeric polysaccharide standardized extract, turmeric and curcumin
standardized powder, and C. longa nonstandardized extract. Clinical
studies were conducted on patients and healthy people by standard-
ized powder of turmeric and curcumin (curcumin C3 complex) in oral
administration by using capsules (26 studies), and also, one study used
curcumin standardized extract in oral administration; and moreover,
curcumin administered intravenously in one study with liposomal
formulation, in total, 2026 individuals participated in clinical studies
people had various conditions including: ulcerative colitis (one study),
Alzheimer (two studies), laparascopic cholecystectomy surgery (one
study), osteoarthritis (four studies), anxiety and fatigue (one study),
healthy (five studies), leukoplakia (one study), pruritus (one study),
diabetes mellitus Type 2 (one study), prediabetic (one study), breast
cancer (one study), obese and diabetic (one study), increased alanine
aminotransferase (one study), metabolic syndrome (one study),
SOLEIMANI ET AL. 3

coronary artery disease (one study), prostate cancer (one study), solid
tumors (one study), major depression disorder (two studies), and
pulmonary problems (one study).
2.1 | Acute toxicity of turmeric/curcumin and
turmeric essential oil in animals
Swiss albino mice that were treated with C. longa nonstandardized
extract orally at the doses of 0.5, 1, and 3 g/kg for investigation of acute
toxicity did not show any sign of toxicity but at the dose of 3 g/kg, some
central nervous system stimulation was observed (Qureshi, Shah, &
Ageel, 1992). In female Lewis rats, intraperitoneal (ip) exposure of
28 mg/kg turmeric essential oil once a day for 2 weeks (this dose was
used for anti‐inflammatory effect of turmeric essential oil) showed
20% of mortality in rats and at the end of the month, 36% of rats died.
Hepatocellular damages, gastrointestinal bleeding, and elevation of
alanine aminotransferase were seen in rats that survived after 1 month.
But there were no mortality, liver damage, gastrointestinal bleeding,
and anemia after oral administration of 560 mg/kg of refined and raw
turmeric essential oil once a day to female Lewis rats for 1 month (Funk,
Frye, Oyarzo, Zhang, & Timmermann, 2010). Also, oral administration
of turmeric essential oil to Wistar rats at single doses of 0.1, 0.25, and
0.5 g/kg body weight did not have acute toxicity and no mortality
was observed, and also, alkaline phosphatase, aspartate aminotransfer-
ase, and alanine aminotransferase did not change compared with ani-
mals that did not receive turmeric essential oil. In addition, there were
no abnormalities in urine tests (Liju, Jeena, & Kuttan, 2013).
Curcumin at the single dose of 5,000 mg/kg body weight that was
given orally to Swiss albino mice did not show any toxic effects during
14 days. In the same way, no toxicity was observed during 14 days in
rats at the single dose of 5,000 mg/kg and no pathological effects were
observed in both rats and mice and no death occurred (Aggarwal,
Chacko, & Kuruvilla, 2016).
In another study, the acute oral toxicity of polysaccharide extracts
from C. longa rhizomes (single dose of 5,000 mg/kg) were evaluated by
oral route to five albino Wistar rats. This study showed that rats did
not have any adverse signs and treated rats with turmeric polysaccha-
ride extract did not show the impairment of the body weight gain
during the 14 days of observation. During these 14 days, the amount
of body weight gain was normal in all treated rats. In addition,
necroscopy did not show any pathological effects in rats treated with
turmeric polysaccharide extract and it was safe at the dose of
5,000 mg/kg to female albino Wistar rats (Velusami et al., 2013). Oral
administration of 0.2% or 1% turmeric to Swiss mice through diet for
14 days showed toxic effects on liver. In this study, the growth of
animals (mice and rats) did not change. Moreover, the liver weight of
mice that received 0.05% ethanolic turmeric extract orally for 14 days
was decreased. Histological studies revealed no abnormality in lungs,
brain, and forestomach tissues in mice that received 1% or 5% turmeric
or 0.05% or 0.25% ethanolic turmeric extract orally compared with
control groups but histological observations revealed changes in liver.
However, histological changes in kidneys and spleen were lesser than
liver. In this study, it was found that animals (female Swiss mice) that
had received 0.01% turmeric did not show anomaly in their liver
sections but cellularity was increased compared with control groups.
Hemoglobin in mice that exposed to 1% or 5% turmeric or 0.05% or
0.25% ethanolic turmeric extract for 14 days did not have any signifi-
cant changes in comparison to control groups. But in mice that
received 1% or 5% turmeric or 0.05% etanolic turmeric extract, signif-
icant increase of serum glutamic oxaloacetic transaminase activity was
observed. Furthermore, in group of mice exposed to 5% turmeric,
serum glutamic pyruvic transaminase activity increased significantly.
In all of doses, the amounts of serum creatinine and urea did not
change but urea levels diminished in the group that received 0.05%
ethanolic turmeric extract (Deshpande et al., 1998).
Nowadays, curcumin may use in nanoformulations for various
uses and so characteristics and oral absorption of curcumin changes
in this form. Thus, it is important to discuss this subject in a separate
article. However, because of the importance of this issue, we briefly
talked about this form of curcumin in animals. In nanoparticles
administered orally (gavage) for 14 days, observation did not show
any fatality and unusual effects in rats. Pathological studies of the
essential organs did not demonstrate any toxicity and also necroscopy
did not show any abnormality. Therefore, curcumin nanoparticles
administered orally were safe at the single dose of 2,000 mg/kg
(Table 1; Dandekar et al., 2010). Male and female Holtzman rats

TABLE 1 Acute toxicity of turmeric/curcumin in animals

Route and duration of administration,
Samples dose Toxicity Mortality Animal Reference

Curcuma longa Orally, 14 days, 0.5, 1, 3 g/kg No toxicity Negative Mice Qureshi et al., 1992
nonstandardized extract
Turmeric essential oil Intraperitoneal, 14 days, 28 mg/kg Hepatotoxicity 20% Mortality Rat Funk et al., 2010
Turmeric essential oil Orally, 14 days, 560 mg/kg No toxicity Negative Rat Funk et al., 2010
Turmeric essential oil Orally, 14 days, 0.1, 0.25, 0.5 g/kg No toxicity Negative Rat Liju et al., 2013
Curcumin Orally, 14 days, 5,000 mg/kg No toxicity Negative Mice and rat Aggarwal et al., 2016
Turmeric polysaccharide Orally, 14 days, 5,000 mg/kg No toxicity Negative Rat Velusami et al., 2013
extract
Solid lipid curcumin Orally, 15 days, 2,000 mg/kg No toxicity Negative Mice and rat Sharma et al., 2004
Curcumin nanoparticles Orally, 14 days, 2,000 mg/kg No toxicity Negative Rat Dandekar et al., 2010
Turmeric ethanolic extract Orally, 14 days, 0.2% or 4% Hepatotoxicity Negative Mice Deshpande et al., 1998
Turmeric ethanolic extract Orally, 14 days, 0.05% Liver weight decreased Negative Mice Deshpande et al., 1998
Turmeric Orally, 14 days 0.01% No toxicity Negative Mice Deshpande et al., 1998
4 SOLEIMANI
are exposed to 100 mg/kg curcumin nanoparticles orally once a day for
28 days. Observations did not indicate any mortality and body weight
did not change. In addition, there were no abnormalities in hematolog-
ical studies and serum biochemical parameters (Dandekar et al., 2010).
In another study, oral administration of solid lipid curcumin
particles to Wistar rats and Swiss albino mice at the single dose of
2,000 mg/kg in 15 days did not show any abnormality in body weight
gain and solid lipid curcumin particles did not have any toxic effects on
Wistar rats and Swiss albino mice. Necroscopy showed no pathological
effects in rats and mice (Sharma et al., 2004).
So in total, turmeric and curcumin are nontoxic in animals although
some mice at certain doses showed changes in liver weight and liver
tissues.
2.2 | Subchronic toxicity of turmeric/curcumin and
turmeric essential oil in animals
To study subchronic toxic effects of curcumin, male and female Swiss
albino mice were exposed to 100 mg/kg of C. longa nonstandardized
extract once daily for 90 days. In this study, the mortality of animals
that received C. longa extract was not significant compared with con-
trol group. In addition, significant changes in weights of vital organs
such as heart and lungs were observed, and also, changes in weight
gain were not significant in treated animals but hematological studies
showed reduction in red blood cell and white blood cell levels (Qureshi
et al., 1992).
No toxic effects were observed in 90‐day study on Wistar albino
rats at the doses of 100, 500, and 1,000 mg/kg body weight of
curcuminoid essential oil given via oral route once a day. Also, no signs
of abnormality and toxicity were seen compared with control groups
(Aggarwal et al., 2016). In another research, oral administration of
5% turmeric to Swiss mice through diet for 90 days demonstrated a
significant decrease in body weight and focal necrosis in liver were
observed (Deshpande et al., 1998). In addition, studies in 13 weeks
(about 90 days) with turmeric essential oil in oral administration to
Wistar rats at doses of 0.1, 0.25, and 0.5 g/kg body weight daily did
not show any mortality and there was no pathological effects in all
of the animals that had received turmeric essential oil. Also, there
were no changes significantly in body weights in both male and
female rats compared with controls. Other experiments such as
histopathological study on liver, kidney, brain, intestine, and spleen
were normal, and serum parameters such as blood urea, serum
electrolytes, serum creatinine, cholesterol, low density lipoprotein,
TABLE 2 Subchronic toxicity of turmeric/curcumin in animals
Route of administration, duration of
Sample administration, dose
Curcuma longa Orally, 90 days, 100 mg/kg
nonstandardized
extract
Curcuminoid essential oil Orally, 90 days, 100, 500, 1,000 mg/kg
Turmeric Orally, 90 days, 5%
Turmeric essential oil Orally, 90 days, 0.1, 0.25, 0.5 g/kg
Curcumin Orally, 70 days, 1,500, 3,000, 10,000 ppm
Note. RBC = red blood cell; WBC = white blood cell.
ET AL.
and very low density lipoprotein cholesterol did not demonstrate
any abnormality (Liju et al., 2013).
Usually, duration of studying subchronic toxicity is 90 days
(Parasuraman, 2011) but in one study that was done during 70 days
in two generations of Wistar rats, curcumin at the concentrations of
1,500, 3,000, and 10,000 ppm (10,000 ppm for the F0 and F1 genera-
tions was equivalent to 847 and 959 mg/kg body weight per day for
male rats and 1,043 and 1,076 mg/kg body weight per day for female
rats) was administered orally through diet to male and female Wistar
rats (doses were according to 28‐day toxicity study). No mortality
was occurred and there were no toxic effects compared with control
groups (Table 2; Ganiger et al., 2007).
Based on the foregoing studies, curcumin and turmeric were safe
in subchronic toxicity studies in animals, especially in rats but signifi-
cant changes in liver tissues in some mice were observed, and also,
red blood cell and white blood cell levels were reduced in one study
in mice.
2.3 | Reproductive toxicity and toxic effects of
turmeric/curcumin in pregnant animals
Studies on Swiss albino mice that received 0.5% of turmeric (0.015%
curcumin) orally through diet for 12 weeks did not show significant
changes in number of dead and live embryos, and also, pregnancy
and implantation rate were normal compared with controls and also
body weight did not change significantly in both rats and mice
(Vijayalaxmi, 1980).
Two generations of male and female Wistar rats that treated with
curcumin at the concentrations of 1,500, 3,000, 10,000 ppm
(10,000 ppm for the F0 and F1 generations was equivalent to 847
and 959 mg/kg body weight per day for male rats and 1,043 and
1,076 mg/kg body weight per day for female rats) orally through diet
did not show reproductive toxicity but at the dose of 10,000 ppm,
body weight gain was reduced a little in F2 generation chicks (Ganiger
et al., 2007). In male nude mice, pegylated curcumin administered
intravenously daily for 10 days. In this study, testicles weights did
not change significantly but seminal vesicles weights and amount of
testicular testosterone diminished and spermatogenesis disturbed
(Murphy, Tang, Van Kirk, Shen, & Murdoch, 2012).
Based on the above‐mentioned studies, oral turmeric and
curcumin administration do not have major toxicity in pregnancy in
animals but more studies should be done.
Toxicity Animal Reference
Change in vital organ weights and Mice Qureshi et al., 1992
reduction in WBC and RBC levels
No toxicity Rats Aggarwal et al., 2016
Decrease in body weight and focal Mice Deshpande et al., 1998
necrosis in liver were observed
No toxicity Rats Liju et al., 2013
No toxicity Rats Ganiger et al., 2007
SOLEIMANI ET AL.
2.4 | Cytotoxic effects of curcumin on normal cell
Curcumin had more cytotoxic effects on cancer cells than normal
cells. In a study for investigation of cytotoxic effects of curcumin
on normal cells (spleen lymphocytes and NIH3T3) and cancer cells
(EL4 and MCF7), curcumin at concentrations of 5 to 80 nmol/ml dem-
onstrated that the uptake of curcumin in cancer cells was higher than
normal cells so cytotoxic effects of curcumin on cancer cells is more
than normal cells (Kunwar et al., 2008). Research projects on human
epithelial pigment cells revealed that concentrations higher than
10 μM of curcumin reduced proliferation of cells, and also, 1 to
50 μM of curcumin decreased the number of living and viable cells
(Hollborn et al., 2013). On vascular smooth muscle cells (VSMCs) and
endothelial cells that isolated from aorta, curcumin showed toxic
effects on normal cells and inhibited cell proliferation at the concen-
tration of 5 μM. At higher concentration of curcumin (10 μM),
VSMCs died.
Also, 2.5 μM curcumin can inhibit proliferation of endothelial cells
and at concentration lower than 1 μM did not have any negative effect
on VSMCs proliferation but endothelial cells proliferation decreased
slightly (Grabowska et al., 2015a).
On ICR albino mice oocytes, curcumin at the concentration of
20 μM showed that maturation, fertilization, growth, and finally fetal
weights were reduced because of exposure to this agent. Also,
reduction in cleavage of oocytes to the two cells and blastocyst cell
numbers were significantly lower than control groups. But the number
of trophectoderm cells in blastocysts did not change significantly. Also,
blastocysts apoptosis increased at the concentration of 20 μM
curcumin. In vivo studies of oocytes that were fertilized and trans-
ferred to the uterus at the blastocyst stage indicated that in female
ICR mice with reasonable diet and water containing 10 to 40 μM of
curcumin, blastocysts implantation rate was decreased. In addition,
the blastocysts development after implantation and the life time of
them were lower than groups that did not receive curcumin (Chen &
Chan, 2012).
In vitro study of ICR mice blastocysts that exposed to 24 μM of
curcumin for 24 hr showed that the elevation of apoptosis and number
of cells were decreased. Also, in vitro studies revealed that 24 μM
curcumin reduced the development rate of morula stage. Furthermore,
for investigation of in vivo study, the blastocysts that treated with
24 μM curcumin showed a reduction in implantation rate and those
TABLE 3 Cytotoxic effects of curcumin
Cell type Concentration
Human retinal pigment epithelial cells >10 μM
Human retinal pigment epithelial cells 1 to 50 μM
Vascular smooth muscle cells 5 μM
Vascular smooth muscle cells 10 μM
Endothelial cells 2.5 μM
ICR albino mice oocyte 20 μM
ICR mice blastocyst 24 μM
Porcine ovarian cell 0, 1, 10, 100 μg/ml
5
blastocysts that implanted could not develop (Chen, Hsieh, Hsuuw,
Huang, & Chan, 2010). In another study, curcumin at the concentration
of 24 μM fatal to all embryos and 6 and 12 μM of curcumin reduced
cell proliferation (Huang et al., 2013). Curcumin at doses of 0, 1, 10,
and 100 μg/ml of medium was studied on porcine ovarian cells. This
research showed that curcumin has apoptotic effects on cells.
Furthermore, cell proliferation and cell viability were reduced and
also, at dose of 100 μg/ml, mortality rate was two times greater than
dose of 0 μg/ml of curcumin (Table 3; Kádasi et al., 2017). So
curcumin has antiproliferative effect in normal cells and can reduce
cell viability.
2.5 | Mutagenicity, chromosomal aberration, and
genotoxicity effects of turmeric/curcumin
Turmeric has many chemical compounds that some of them are non-
toxic and nonmutagenic and some of them are toxic and mutagenic
but its major constituent is curcumin that has dose dependent toxic
effects (Balaji & Chempakam, 2010). In Ames salmonella mutagenic-
ity test, the ethanolic extract of turmeric at the concentrations of
50,100 and 200 μg/plate before and after activation with mamma-
lian bowel microflora and hepatic microsomal enzymes did not show
any mutagenicity in this assay (Shah & Netrawali, 1988). Turmeric
essential oil did not induce mutagenicity in Salmonella typhimurium.
In addition, in male and female rats that received a single dose of
turmeric essential oil (1 g/kg) for 14 days, no significant DNA dam-
age and chromosomal aberration were observed (Liju et al., 2013).
At concentrations of 5,000 μg/ml of turmeric polysaccharide extract,
no toxicity in bacteria was occurred and also it was not mutagenic
up to 5,000 μg/ml. Also, there was no chromosomal aberration in
human blood lymphocytes at concentrations of 250.36 to
2,500 μg/ml of turmeric polysaccharide extract (Velusami et al.,
2013). Swiss albino mice that received 0.5% of turmeric (0.015%
curcumin) through their diet for about 12 weeks did not show
abnormalities in number and structure of bone marrow
chromosomes, and also, mutagenic effect was not observed. In
addition in this study, Wistar rats that received 0.05% and 0.05%
of turmeric through diet did not show abnormality in bone marrow
chromosomes (Vijayalaxmi, 1980). So turmeric and curcumin are
nonmutagenic and nongenotoxic.
Result Reference
Reduction in proliferation Hollborn et al., 2013
Increase in cell Hollborn et al., 2013
Cells proliferation stopped Grabowska et al., 2015b
Number of living cells were reduced Grabowska et al., 2015b
Cells proliferation stopped Grabowska et al., 2015a
Reduction in maturation, fertilization and Chen & Chan, 2012
growth but apoptosis increased
Apoptosis increased, number of cells, and Chen et al., 2010
implantation rate were reduced
Curcumin had apoptotic effect and cell Kádasi et al., 2017
proliferation and cell viability were reduced
6 SOLEIMANI
2.6 | Safety and toxicity evaluation of turmeric/
curcumin in human double‐blind, randomized, placebo‐
controlled clinical trials
Study on patients with ulcerative colitis who had received 2 g/day
curcumin orally for 6 months did not show major toxic effects but
flatulence was observed (Hanai et al., 2006). The oral intake of 1 or
4 g/day curcumin for 6 months in patients with Alzheimer's disease
was well tolerated and did not show any intense adverse effects
(Baum et al., 2008). Furthermore, in another study on patients with
Alzheimer's disease, 0.2 or 4 g/day of curcuminoids administered orally
for 24 weeks was also well tolerated (Ringman et al., 2012). No toxic
effects were observed in 50 individuals who treated with 500 mg
curcumin every 6 hr for 3 weeks after laparoscopic cholecystectomy
surgery (Agarwal, Tripathi, Agarwal, & Saluja, 2011).
The oral intake of 1 g/day of curcumin for 3 months did not show
toxicity in patients with osteoarthritis (Pinsornsak & Niempoog, 2012).
In another study on these patients, 180 mg curcumin administered
daily via oral route for 8 weeks. In this research, no major toxicity
was reported but hypertension and tachycardia were reported in one
person and also redness of tongue was observed in another person
(Nakagawa et al., 2014). In other clinical research projects, no major
toxicity was reported in patients with osteoarthritis who treated with
1,500 mg/day of curcuminoids orally for 6 weeks and patients who
received 1.5 g/day curcumin within 6 weeks (Panahi, Rahimnia, et al.,
2014; Rahimnia, Panahi, Alishiri, Sharafi, & Sahebkar, 2015). There
were no severe adverse events in prediabetic individuals who received
1.5 g/day curcumin for 3 months, but itching was reported in one
patient and constipation was observed in two patients (Chuengsamarn,
Rattanamongkolgul, Luechapudiporn, Phisalaphong, & Jirawatnotai,
2012). Curcumin at the dose of 1,500 mg/day orally during 6 months
in 240 patients with Type 2 diabetes mellitus did not show severe side
effects but constipation and nausea occurred in some patients
(Chuengsamarn, Rattanamongkolgul, Phonrat, Tungtrongchitr, &
Jirawatnotai, 2014). Gastrointestinal events were observed in some
patients with pruritus caused by sulphur‐mustard who had received
1 g/day of curcumin for 4 weeks. In addition, some patients left the
experiment due to gastrointestinal side effects but there were no
major toxic effects (Panahi, Sahebkar, Amiri, et al., 2012). In patients
with breast cancer, no severe adverse reactions were observed with
oral intake of 6 g/day of curcumin within 4–7 weeks and it was safe
(Ryan et al., 2013). In one research on 45 postmenopausal and not
active women, the intake of 150 mg/day curcumin for 8 weeks via oral
route did not demonstrate toxic effects and it was well tolerated
(Sugawara et al., 2012).
There were no severe adverse reactions in 100 diabetic and obese
patients who received 300 mg/day of curcuminoids (36.06% curcumin,
18.85% demethoxycurcumin, and 42.58% bisdemethoxycurcumin)
during 3 months, but changes in liver enzymes and biochemical param-
eters of blood were observed (Na et al., 2013). In patients with fatty
liver disease, the intake of 500 mg curcumin formulation (containing
70 mg curcumin) daily for 8 weeks was tolerable (Rahmani et al.,
2016). Fermented turmeric at the dose of 4 g/day (containing
0.79 mg curcumin/g) orally for 12 weeks was not toxic in individuals
with mild to moderate increased alanine transaminase (Kim et al.,
ET AL.
2013). A single dose of intravenous administration of liposomal
curcumin to 50 healthy male and female subjects was safe at the doses
of less than 120 mg/m2 but at higher doses, the morphology of red
blood cells was changed (Storka et al., 2015). In two patients with met-
abolic syndrome, the oral administration of 1,890 mg of curcumin
extract during 12 weeks (containing curcumin, demethoxycurcumin,
and bisdemethoxycurcumin) caused nausea and diarrhea (Yang et al.,
2014). Stomachache and flatulence were observed in one patient (of
56 patients) with major depressive disorder at the dose of 1,000 mg/
day curcumin within 8 weeks (Lopresti, Maes, Maker, Hood, & Drum-
mond, 2014). In addition, in another trial on 40 patients with depres-
sion, no side effects were reported with 500 mg curcumin that
administered daily via oral route for 5 weeks (Bergman et al., 2013).
Some adverse effects such as constipation, stomachache, and head-
ache were observed in patients with pulmonary problems induced by
sulphur mustard who received 1.5 g/day curcumin during 4 weeks,
but major toxicity and severe adverse effects were not occurred
(Panahi, Ghanei, Bashiri, Hajihashemi, & Sahebkar, 2015). There were
no adverse events in studies on patients with solid tumors during
8 weeks with oral intake of 900 mg/day curcumin, although a little
gastrointestinal upset was reported (Panahi, Saadat, Beiraghdar,
Nouzari, et al., 2014; Panahi, Saadat, Beiraghdar, & Sahebkar, 2014).
In a double‐blind trial, patients with coronary artery disease received
capsules (500 mg of curcumin or placebo) four times in a day for
8 weeks. In this study, just two patients had some gastrointestinal
symptoms such as diarrhea. In addition in this study, urea, creatinine,
and high‐density lipoprotein cholesterol did not change significantly
compared with placebo group (Mirzabeigi et al., 2015). In patients with
prostate cancer, 3 g curcumin administered daily within 9 weeks and
no side effects were reported in this trial (Hejazi, Rastmanesh, Taleban,
Molana, & Ehtejab, 2013). In a study on healthy mature individuals, oral
intake of 400 mg curcumin daily for 4 weeks did not show toxicity and
it was safe at this dose (Cox, Pipingas, & Scholey, 2015), as well as no
adverse effects were observed in healthy young people who received
200 mg curcumin by mouth within 8 weeks (Oliver et al., 2016).
Curcumin was safe in patients with leukoplakia at the dose of
3.6 g/day orally for 6 months and no severe side effects were reported
(Kuriakose et al., 2016).
In a clinical study on healthy women, 100 mg curcumin adminis-
tered orally every 12 hr during 3 cycles of premenstrual syndrome
(each cycle lasted 10 days). In this research, no side effects and toxicity
were reported (Fanaei, Khayat, Kasaeian, & Javadimehr, 2016).
Patients with anxiety and fatigue treated with 500 mg curcumin twice
a day for 30 days; in this trial, the formulation of curcumin had good
bioavailability and could pass through the blood–brain barrier. In this
trial, curcumin was well tolerated and was safe (Table 4; Pandaran
Sudheeran et al., 2016). Curcumin was known as a generally recog-
nized as safe substance by the US Food and Drug Administration
(Agrawal & Goel, 2016).
So these studies showed that turmeric and curcumin in the form of
standardized powder and extract are nontoxic in human, and also,
bioavailable formulations such as nanoformulations were safe but
studies on these formulations are low and more studies are needed
and the toxicity of bioavailable formulations and nanoformulations
should be discussed in detail in a separate article.
SOLEIMANI ET AL.
TABLE 4 Safety and toxicity of turmeric/curcumin in human double‐blind, randomized, placebo controlled clinical trials
Patient/healthy
Patients with ulcerative colitis
Patients with Alzheimer's disease
Patients with Alzheimer's disease
Patients after laparascopic
cholecystectomy surgery
Patients with osteoarthritis
Patients with anxiety and fatigue
Healthy women
Patients with leukoplakia
Patients with osteoarthritis
Patients with osteoarthritis
Prediabetic patients
Patients with Type 2
diabetes mellitus
Patients with breast cancer
Healthy postmenopausal and
not active women
Diabetic and obese patients
Patients with mild to moderate
increased alanine
transaminase (ALT)
Healthy young people
Healthy individuals
Patients with metabolic
syndrome
Patients with coronary
artery disease
Healthy mature individuals
Patients with prostate cancer
Patients with solid tumors
Patients with pulmonary problems
induced by sulphur mustard
Patients with depression
Patient with major depressive
disorder (MDD)
Patients with pruritus caused
by sulphur‐mustard
2.7 | Conventional drugs interactions with
curcuminoids
Curcumin has inhibitory effect on a number of cytochrome P450 sub-
types, for example, in human, it can inhibit highly CYP2C9 (Wang et al.,
7
Duration and route of administration,
curcumin/turmeric dose Toxicity Reference
6 months orally 2 g/day curcumin No major toxicity but Hanai et al., 2006
flatulence was observed
6 months orally 1 or 4 g/day curcumin No toxicity Baum et al., 2008
24 weeks orally 0.2 or 4 g/day curcumin No toxicity Ringman et al., 2012
3 weeks orally 2 g/day curcumin No toxicity Agarwal et al., 2011
3 months orally 1 g/day curcumin No toxicity Pinsornsak & Niempoog,
2012
30 days orally 1,000 mg/day curcumin No toxicity Pandaran Sudheeran
(bioavailable formulation) et al., 2016
3 cycles of premenstrual syndrome No toxicity Fanaei et al., 2016
(each cycle lasted 10 days) orally
200 mg/day curcumin
6 months orally 3.6 g/day curcumin No toxicity Kuriakose et al., 2016
8 weeks orally 180 mg/day curcumin No major toxicity was reported but Nakagawa et al., 2014
hypertension, tachycardia, and
redness of tongue were reported
6 weeks orally 1,500 mg/day curcumin No toxicity Rahimnia et al., 2015; Panahi,
Rahimnia, et al., 2014
6 months orally 1.5 g/day curcumin Safe but itching in one patient and Chuengsamarn et al., 2012
constipation in two patients
were reported
6 months orally 1,500 mg/day curcumin No major toxicity but nausea and Chuengsamarn et al., 2014
constipation were observed
4–7 weeks orally 6 g/day curcumin No toxicity Ryan et al., 2013
8 weeks orally 150 mg/day curcumin No toxicity Sugawara et al., 2012
3 months orally 300 mg/day curcumin No major toxicity but changes in Na et al., 2013
liver enzymes and biochemical
parameters of blood were
observed
12 weeks orally 4 g/day of No toxicity Kim et al., 2013
fermented turmeric
8 weeks orally 200 mg/day curcumin No toxicity Oliver et al., 2016
Intravenous single dose of 120 mg/m2 Safe but morphology of red blood Storka et al., 2015
liposomal curcumin cells was changed at higher doses
12 weeks orally 1,890 mg No major toxicity but nausea Yang et al., 2014
curcumin extract and diarrhea were reported
8 weeks orally 2 g/day curcumin No major toxicity but diarrhea Mirzabeigi et al., 2015
was observed
4 weeks orally 400 mg/day curcumin No toxicity Cox et al., 2015
9 weeks orally 3 g curcumin No toxicity Hejazi et al., 2013
8 weeks orally 900 mg/day curcumin No toxicity Panahi, Saadat, Beiraghdar,
Nouzari, et al., 2014;
Panahi, Saadat, Beiraghdar,
& Sahebkar, 2014
4 weeks orally 1.5 g/day curcumin No toxicity Panahi et al., 2015
5 weeks orally 500 mg/day curcumin No toxicity Bergman et al., 2013
8 weeks orally 1,000 mg/day curcumin No major toxicity but stomachache Lopresti et al., 2014
and flatulence were observed
4 weeks orally 1 g/day curcumin No major toxicity but gastrointestinal Panahi, Sahebkar, Amiri,
side effects were reported et al., 2012
2015). Curcuminoids (curcumin, demethoxycurcumin, and bisdemetho-
xycurcumin; Figure 2) inhibited some cytochromes P450 such as
CYP3A4 and also UDP‐glucuronosyltransferase and sulfotransferase
(Volak, Ghirmai, Cashman, & Court, 2008). Owing to its effect on cyto-
chromes P450, turmeric can potentially interact with some medications.
8 SOLEIMANI
Curcuminoids influence the pharmacokinetic of some different conven-
tional drugs such as anticoagulants, antibiotics, cardiovascular drugs,
anticancer drugs, and antidepressants, for example, total area under the
curve of clopidogrel increased at the dose of 100 mg/kg of curcumin
due to inhibition of P‐glycoprotein, and moreover, curcuminoids affect
the pharmacokinetic of warfarin, however, some drugs such as paraceta-
mol did not have interactions with curcuminoids (Bahramsoltani, Rahimi,
& Farzaei, 2017; Liu, Zhao, & Lou, 2013). Therefore, a clinical attention to
interactions is important when prescribing curcumin and turmeric with
conventional drugs at the same time.
3 | C O N CL U S I O N
Many studies have explored the safety of turmeric and curcumin.
These studies have been conducted on cell culture, animals, and some
of them were done on healthy people and patients. According to these
studies, standardized powder and extract of turmeric and curcumin are
safe for human use even at high doses. For example, oral administra-
tion of curcumin at the dose of 6 g/day for 4–7 weeks was safe in
human. It should be mentioned that curcumin may be absorbed at
low amounts in gastrointestinal system. However, bioavailable for-
mulations in animals and humans did not have major toxicity but
more studies are needed to substantiate this issue. Curcumin was
also found to be safe at certain doses (lower than oral doses) in
intravenous administration in human. Oral administration of tur-
meric/curcumin (standardized powder and extract) to animals did
not show any major toxic effects. In cell culture studies, cell prolifer-
ation and cell viability can be affected in normal cells and they
would be reduced at certain concentrations. In addition, curcumin
is a nonmutagenic and nongenotoxic agent. In pregnancy, curcumin
was safe in animals but more studies are needed to confirm its
safety in pregnant women. The review's limitations were lack of
long‐term data, enough information on the safety of parenteral
forms, studies on pregnant women, and enough dose escalation
studies in humans. Moreover, in this review only English language
articles were evaluated. In total, it can be concluded that turmeric
and curcumin are safe; however, further studies are needed on var-
ious formulations of curcumin especially in humans.
CONF LICT OF INTE R ES T
The authors declare that they have no conflict of interest.
ET AL.
FIGURE 2 Curcuminoids structure
ORCID
Amirhossein Sahebkar http://orcid.org/0000-0002-8656-1444
Hossein Hosseinzadeh http://orcid.org/0000-0002-3483-851X
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How to cite this article: Soleimani V, Sahebkar A, Hosseinzadeh
H. Turmeric (Curcuma longa) and its major constituent (curcumin)
as nontoxic and safe substances: Review. Phytotherapy Research.
2018;1–11. https://doi.org/10.1002/ptr.6054