Received: 16 December 2020 Revised: 16 June 2021 Accepted: 14 August 2021

DOI: 10.1002/ptr.7264

REVIEW

Current clinical developments in curcumin-based therapeutics

for cancer and chronic diseases

Aviral Kumar1 | Choudhary Harsha1 | Dey Parama1 | Sosmitha Girisa1 |

Uzini Devi Daimary1 | Xinliang Mao2 | Ajaikumar B. Kunnumakkara1

1
Cancer Biology Laboratory and DBT-AIST
International Center for Translational and
Environmental Research (DAICENTER),
Department of Biosciences and
Bioengineering, Indian Institute of Technology
(IIT) Guwahati, Guwahati, India
2
Institute of Clinical Pharmacology,
Guangzhou University of Chinese Medicine,
Guangzhou, China
Correspondence
Ajaikumar B. Kunnumakkara, Cancer Biology
Laboratory and DBT-AIST International Center
for Translational and Environmental Research
(DAICENTER), Department of Biosciences and
Bioengineering, Indian Institute of Technology
(IIT) Guwahati, Guwahati, Assam 781039,
India.
Email: kunnumakkara@iitg.ac.in
Funding information
DAICENTER
The last decade has seen an unprecedented rise in the prevalence of chronic diseases
worldwide. Different mono-targeted approaches have been devised to treat these
multigenic diseases, still most of them suffer from limited success due to the off-
target debilitating side effects and their inability to target multiple pathways. Hence a
safe, efficacious, and multi-targeted approach is the need for the hour to circumvent
these challenging chronic diseases. Curcumin, a natural compound extracted from
the rhizomes of Curcuma longa, has been under intense scrutiny for its wide medicinal
and biological properties. Curcumin is known to manifest antibacterial,
antiinflammatory, antioxidant, antifungal, antineoplastic, antifungal, and proapoptotic
effects. A plethora of literature has already established the immense promise of
curcuminoids in the treatment and clinical management of various chronic diseases
like cancer, cardiovascular, metabolic, neurological, inflammatory, and infectious dis-
eases. To date, more than 230 clinical trials have opened investigations to understand
the pharmacological aspects of curcumin in human systems. Still, further randomized
clinical studies in different ethnic populations warrant its transition to a marketed
drug. This review summarizes the results from different clinical trials of curcumin-
based therapeutics in the prevention and treatment of various chronic diseases.

KEYWORDS
bioavailability, chronic diseases, clinical trials, curcumin

1 | I N T RO DU CT I O N complications in chronic diseases (Khwairakpam et al., 2020;

Kunnumakkara, Sailo, et al., 2018; Roy et al., 2019; Schmidt, 2016).
Chronic diseases are noncommunicable diseases that have been con- Despite having considerable progress made in the therapeutic regi-
sidered a significant detrimental health hazard around the globe. It is mens, the incidence rate of chronic diseases has seen an unprece-
estimated that three-quarters of all deaths worldwide are due to dented increase worldwide (Gupta, Patchva, Koh, & Aggarwal, 2012;

Abbreviations: ALT, Alanine aminotransferase; AR, Androgen receptor; AST, Aspartate transaminase; Bcl-2, B-cell lymphoma protein 2; Bcl-xL, B-cell lymphoma-extra-large; Ca2+PK, Ca2
+-dependent protein kinase; CDKs, cyclin-dependent kinases; cIAP, Cellular inhibitor of apoptosis protein; CXCR4, Chemokine (C-X-C motif) receptor 4; COX-2, Cyclooxygenase-2; CTGF,
Connective-tissue growth factor; DNMT1, DNA (cytosine-5)-methyltransferase-1; EGF, Epidermal growth factor; EGFR, Epidermal growth factor receptor; ERE, Estrogen response elements;
ERG, Erythroblast transformation-specific related gene; ERK, Extracellular signal-regulated kinase; FADD, Fas-associated protein with death domain; FGF, Fibroblast growth factor; H2R,
Histamine H2 receptor; HIF-1, Hypoxia inducible factor-1; ICAM-1, Intracellular adhesion molecule-1; IFN, Interferon; IKK, IκB kinase; IL-1, Interleukin-1; IL-2, Interleukin-2; IL-5, Interleukin-5;
IL-6, Interleukin-6; IL-8, Interleukin-8; IL-12, Interleukin-12; IL-18, Interleukin-18; IL-1R, Interleukin-1 receptor; IL-1 RAK, Interleukin-1 receptor-associated kinase; ITPR, Inositol 1,4,5-
triphosphate receptor; JAK, Janus kinase; JNK, c-Jun amino-terminal kinase; LDL-R, Low-density lipoprotein receptor; 5-LOX, 5-lipoxygenase; MAPK, Mitogen-activated protein kinase; MCP-1,
Monocyte chemotactic protein-1; NF-κB, Nuclear factor kappa B; Nrf2, Nuclear factor erythroid 2-related factor 2; PARP, Poly (ADP-ribose) polymerase; PCNA, Proliferating cell nuclear antigen;
PI3K, Phosphatidylinositol 3-kinase; PKA/B/C, Protein kinase A/B/C; PPAR-γ, Peroxisome proliferator-activated receptor gamma; STAT, Signal transducer and activator of transcription; TF,
Tissue factor; TGF, Transforming growth factor; TGF-β1, Transforming growth factor beta 1; TMMP-3, Tissue inhibitor of metalloproteinase-3; TNF, Tumor necrosis factor; uPA, Urokinase-type
plasminogen activator; VEGF, Vascular endothelial growth factor.

Phytotherapy Research. 2021;1–34. wileyonlinelibrary.com/journal/ptr © 2021 John Wiley & Sons Ltd. 1
2 KUMAR ET AL.
Kunnumakkara, Banik, et al., 2018; Padmavathi et al., 2017).
According to the World Health Organization (WHO), the prevalence
of chronic diseases is expected to rise by 57% by 2020. This could be
due to changes in societal behavior, improper nutrition, tobacco use,
excessive alcohol consumption, and other risk factors associated with
these multigenic diseases (S. Patel, Ram, Patel, & Kumar, 2019). Fur-
thermore, the mono-targeted approaches currently being employed
have met with a limited clinical response due to their incapability to
target multiple signaling pathways and debilitating side effects
(Bordoloi, Roy, Monisha, Padmavathi, & Kunnumakkara, 2016; Hsieh,
Yang, Sethi, & Hu, 2015; Li et al., 2013). Innovations in understanding
the disease pathophysiology have brought a rapid change in develop-
ing novel therapeutic regimens (Manu et al., 2014; Swaminathan
et al., 2021). With further causatives and mechanisms being impli-
cated for these multigenic diseases, there exists a need for the identi-
fication of molecules that are safe, efficacious, robust, multi-targeted,
nontoxic, and also low cost in order to replace the existing ineffica-
cious and toxic therapeutics and circumvent these diseases (Gupta
et al., 2012; A. Nair, Amalraj, Jacob, Kunnumakkara, & Gopi, 2019;
Shanmugam et al., 2012; S. F. Yang, Weng, Sethi, & Hu, 2013).
Natural extracts from plants have long been used since ancient
times to treat multiple disorders (Kashyap et al., 2019; Lee
et al., 2014; Liu et al., 2015; S. M. Patel, Nagulapalli Venkata,
Bhattacharyya, Sethi, & Bishayee, 2016; Shishodia, Sethi, Ahn, &
Aggarwal, 2007). Various preclinical and clinical experimentations
have reported the role of these extracts in inhibiting the deleterious
effects and for the proper management of the diseases (Banik
et al., 2020; Bordoloi et al., 2019; Daimary et al., 2021; Garodia,
Girisa, Rana, Kunnumakkara, & Aggarwal, 2020; Harsha, Banik,
Bordoloi, & Kunnumakkara, 2017; Khwairakpam et al., 2018;
Khwairakpam et al., 2018; Khwairakpam et al., 2019; C. Kim
et al., 2014; Kunnumakkara, Nair, et al., 2007; Kunnumakkara, Chung,
Koca, & Dey, 2009; Lee, Kim, Sethi, & Ahn, 2015; Li et al., 2013; Manu
et al., 2015; Padmavathi et al., 2015; Parama et al., 2020; Ranaware
et al., 2018; Singh et al., 2019). Curcumin, a natural polyphenol
extracted from the rhizomes of Curcuma longa, has long been in the
center of researchers' attention due to its immense clinical and phar-
macological properties (Anand, Kunnumakkara, & Aggarwal, 2009;
Hatcher, Planalp, Cho, Torti, & Torti, 2008; Kunnumakkara, Harsha,
et al., 2019; Moballegh Nasery et al., 2020; Prasad, Gupta, Tyagi, &
Aggarwal, 2014; Shabnam, Harsha, Thakur, Khatoon, & Rashidinejad, Melton, & McGillivray, 2021; Sanidad, Sukamtoh, Xiao,
Kunnumakkara, 2021). This golden nutraceutical has been well studied
and experimented with 16,000 citations in PUBMED and 200 clinical
trials for different chronic diseases. A plethora of literature has
already associated curcumin as a potent antiinflammatory, antiviral,
antioxidant, antimicrobial, antiatherosclerotic, antidepressant,
antiarthritic, and wound healing properties (Aggarwal, Yuan, Li, &
Gupta, 2013; Girisa et al., 2021). Moreover, it is also implicated to
exhibit chemoprotective and chemosensitive, and radioprotective and
radiosensitive properties in response to the debilitating effects of con-
ventional therapeutics (Goel & Aggarwal, 2010; Gupta et al., 2011;
Shanmugam, Kannaiyan, & Sethi, 2011; Tewari et al., 2018). Curcumin
has the potential to target diverse molecules and multiple cellular
pathways, including nuclear factor kappa B (NF-κB), cyclooxygenase-2
(COX-2), cytokines molecules, transforming growth factor beta (TGF-
β), C-reactive proteins (CRPs), apoptotic proteins, creatinine, adhesion
molecules, alanine aminotransferase (ALT), aspartate transaminase,
and phosphorylase kinases (Deng et al., 2019; Kunnumakkara,
Bordoloi, Padmavathi, et al., 2017; Puar et al., 2018). Studies over the
past decades already suggest curcumin's multi-mechanistic mode of
action in combating different types of chronic diseases like pro-
inflammatory diseases, cancer, diabetes, obesity, atherosclerosis,
depression, and neurodegenerative diseases (Aggarwal, Gupta, &
Sung, 2013; Aggarwal, Yuan, et al., 2013; Gupta et al., 2013;
Shanmugam, Warrier, Kumar, Sethi, & Arfuso, 2017). Curcumin exists
in two tautomeric forms (keto and enol), and both of them display
anti-inflammatory, anti-viral, high anti-microbial, and anti-cancer prop-
erties (Aggarwal et al., 2008; Goel, Kunnumakkara, & Aggarwal, 2008;
Gupta et al., 2012; Gupta, Kim, Prasad, & Aggarwal, 2010; Mishra
et al., 2019; Rainey, Motte, Aggarwal, & Petit, 2015). Accumulating
evidence suggests that the structure of curcumin, which includes
double-conjugated bonds, bis-α, β-unsaturated β-diketone, phenolic
hydroxy groups, and methoxy groups are responsible for its anti-
inflammatory and anti-proliferative attributes. Curcumin has already
been approved as Generally Recognized as Safe (GRAS) by the US
Food and Drug Administration (FDA) and is recognized to increase the
overall biological functions of individuals (Aggarwal, Gupta,
et al., 2013; Cuomo et al., 2011). Owing to its high pleiotropic proper-
ties, many companies provide curcumin as a nutraceutical in the form
of capsules, drinks, creams, tablets, extracts, gels, nasal sprays, and
other products of medicinal value (Prasad, Tyagi, & Aggarwal, 2014).
Although curcumin has tremendous potential in curbing varied
chronic diseases, it has still not been able to reach the clinics as a
marketed drug due to its low bioavailability in the living system
and unsuitable pharmacodynamics (Anand, Sundaram, Jhurani,
Kunnumakkara, & Aggarwal, 2008; Shanmugam et al., 2015). It is
quickly eliminated from the system without being absorbed properly.
To overcome these limitations, different strategies have been devel-
oped to increase the bioavailability of curcumin in the human systems
that include chemically modified analogs, nanoparticle formulations,
reformulating with different oils and polymers, conjugating with other
natural compounds, etc. (Anand, Kunnumakkara, Newman, &
Aggarwal, 2007; Goel et al., 2008; H. B. Nair et al., 2010; Sabet,
McClements, & Zhang, 2019). As bisdemethoxycurcumin and
demethoxycurcumin, two natural analogs of curcumin, also have simi-
lar drawbacks, several chemical modifications have been developed
like the addition of phenolic hydroxyl groups, acyl groups, aminoacyl
moieties, alkylation, and glycosylation to increase the bioavailability of
these compounds (Kocaadam & Şanlier, 2017; Sahu, Sahu, Sahu, &
Agarwal, 2016). Recent investigations using different nano-
formulations of curcumin have opened newer frontiers in increasing
the bioavailability of this compound (Dei Cas & Ghidoni, 2019).
THERACURMIN®, a highly bioavailable form of curcumin, is fabri-
cated using surface-controlled colloidal dispersion. Other studies have
widely explored various other forms of curcumin like lipid-based
KUMAR ET AL. 3

formulations, micellar nano-structures, curcumin conjugated to poly-
mers, self-micro-emulsifying systems, etc. (Mandal, Jaiswal, &
Mishra, 2020). Mucoadhesive polymers conjugated with curcumin
helps in increasing its stability and allows prolonged delivery (Ma,
Wang, He, & Tang, 2019). Novel strategies using extracellular vesicle
systems to encapsulate curcumin or curcumin primed exosomes are
ongoing as they offer superior pharmacokinetic attributes than exis-
ting approaches (Oskouie, Aghili Moghaddam, Butler, Zamani, &
Sahebkar, 2019). It is evident from a large number of ongoing clinical
trials and a plethora of preclinical studies that curcumin's wide pleio-
tropic attributes far overshadow its low bioavailability. Thus, curcumin
could hold immense potential in the clinical management of various
chronic diseases by providing overall immunity and abrogating the
cascade of signaling events. Still, to validate the authenticity and
effectiveness of any therapeutics, proper randomized, double-blind
clinical trials are crucial in generating and providing the data needed
to proceed into the markets. This review highlights the outcomes of
numerous clinical trials of curcumin for chronic diseases and provides
a compendium for further research and development of curcuminoid
therapeutics as a marketed drug.
2 | MOLECULAR TARGETS OF CURCUMIN
Curcumin is a multi-targeted polyphenol, and multiple shreds of evi-
dence over the years have evidenced that it can modulate a wide vari-
ety of molecular targets and signaling pathways that are responsible
for the development and progression of various chronic diseases
(Figure 1). It can effectively regulate the expression of the critical ele-
ments of the cell signaling pathways such as phosphatidylinositol
3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of
rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extra-
cellular signal-regulated kinase (ERK), janus kinase (JAK)/signal trans-
ducer and activator of transcription (STAT), NF-κB, Wnt/β-catenin,
etc. It has the ability to target different proteins such as nuclear
factor erythroid 2-related factor 2 (Nrf2), DNA (cytosine-5)-
methyltransferase-1, COX-2, 5-lipoxygenase, prostaglandin 2 (PGE2),
forkhead box protein O3 (FOXO3), inducible nitric oxide synthase
(iNOS), reactive oxygen species (ROS), cyclin D1, vascular endothelial
growth factor (VEGF), glutathione, cytosolic phospholipase A2, and p-
Tau (Aggarwal et al., 2006; Aggarwal, Deb, & Prasad, 2014; Anand,
Sundaram, et al., 2008; Fang, Chen, Huang, Chen, & Liao, 2018;
Harsha et al., 2020; H. Y. Kim, Park, Joe, & Jou, 2003; Kunnumakkara,
Guha, et al., 2007; Kunnumakkara et al., 2008; Kunnumakkara,
Bordoloi, Harsha, et al., 2017; Kunnumakkara et al., 2020;
Kunnumakkara, Bordoloi, Padmavathi, et al., 2017; Lin et al., 2007;
Monisha et al., 2016; Rafiee et al., 2010; Ramasamy, Ayob, Myint,
Thiagarajah, & Amini, 2015). Its molecular targets comprise a varied
range of transcription factors, enzymes, growth factors, inflammatory
cytokines, cell surface receptors, adhesion molecules, and several
others that play an important role in disease progression (Aggarwal,
Sethi, Baladandayuthapani, Krishnan, & Shishodia, 2007; Ahn, Sethi,
Jain, Jaiswal, & Aggarwal, 2006). It exerts significant inflammatory
activities via inhibiting the inflammatory cytokines such as tumor

Metabolic diseases
Cardiovascular
Cancer Diabetes
diseases
Breast Cancer Obesity
Acute coronary
Cervical cancer Diabetic
syndrome
Colorectal Caner microangiopathy
Acute myocardial
Head and neck Cancer Diabetic neuropathy
infarction
Lung cancer Dyslipidaemia

Skin diseases
Inflammatory diseases Dermatitis
Biliary diseases Psoriasis
Bronchial asthma Vitiligo
Crohn’s disease Curcumin
Chronic anterior uveitis
Chronic cutaneous complications Others
Chronic periodontitis Alcohol intoxication
Gingivitis β-thalassemia
Oral lichen planus Biliary dyskinesia
Chronic pulmonary Neurological Cholecystitis
complications diseases Viral diseases Chronic arsenic exposure
Chronic kidney disease Alzheimer Acquired Chronic bacterial prostatitis
Gastritis diseases immunodeficiency Gallbladder contraction
Inflammatory bowel disease Depression syndrome Hepatoprotection
Osteoarthritis Schizophrenia Hepatic infections Recurrent respiratory tract-
Peptic ulcer infections
Rheumatoid arthritis Renal transplantation
Ulcerative colitis

F I G U R E 1 Therapeutic potential of curcumin against different chronic diseases like cancer, cardiovascular, metabolic, neurological,
inflammatory, skin, and infectious diseases [Colour figure can be viewed at wileyonlinelibrary.com]
4 KUMAR ET AL.
necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-6, IL-12, and IL-1β,
etc. (Aggarwal & Sung, 2009; Bharti, Takada, & Aggarwal, 2004; Davis
et al., 2007; Kunnumakkara, Bordoloi, Padmavathi, et al., 2017; Sethi,
Sung, Kunnumakkara, & Aggarwal, 2009). It also inhibits proliferation
and induces apoptosis, two of the critical cellular events, by modulat-
ing the expression of different apoptotic proteins such as p53, cyclin-
dependent kinases (CDKs), B-cell lymphoma 2 (Bcl2), B-cell
lymphoma-extra-large (Bcl-xl), survivin, inhibitor of apoptosis (IAP)-1,
and IAP-2 (Han, Chung, Robertson, Ranjan, & Bondada, 1999; Park
et al., 2002; Woo et al., 2003). Also, numerous studies over the years
have revealed its role in the regulation of angiogenesis via inhibiting
the angiogenic factor VEGF and migration and invasion of cells by
suppressing matrix metalloproteinase (MMP-9) (Cao et al., 2014;
Mathew & Sarada, 2018). Further, it can aid in cancer cell
chemosensitization by downregulating the expression of various
multidrug resistance genes (Bordoloi et al., 2016; Khatoon
et al., 2020). Recent studies have also demonstrated the potential of
curcumin in controlling epigenetic pathways mainly via aiding histone
modifications and suppressing DNA methyltransferase, histone
deacetylase, and acetyltransferase (Boyanapalli & Kong, 2015;
Merarchi et al., 2019). Curcumin was also found to upregulate the
expression of tumor suppressor microRNAs such as miR-22, miR-15a,
and miR-16 in vitro (Sun et al., 2008; J. Yang, Cao, Sun, &
Zhang, 2010). Thus, the overwhelming outcomes of the preclinical
studies and the revelation of such a varied range of molecular targets
have interested researchers worldwide to evaluate the potential of
this golden nutraceutical in clinical settings.
3 | C L I N I C A L S T U DI ES W I T H CU RC U M I N
Curcumin's wide pleiotropic attributes have been extensively studied,
and numerous clinical trials have already been completed to showcase
the potential of this compound for various chronic diseases (Table 1).
Promising clinical outcomes have started newer investigations in
studying the in-depth mechanism and evaluating the pharmacokinet-
ics of curcumin therapy in combination with other conventional thera-
pies in the treatment and palliative care for chronic diseases (Table 2).
3.1 | Safety profile of curcumin
Curcumin, as a dietary agent, has been recognized as “generally safe”
by the FDA (U.S. FDA, 2013). The adequate daily intake value rec-
ommended for this therapeutic molecule by the Joint FAO/WHO
Expert Committee on Food Additives (JECFA) and European Food
Safety Authority (EFSA) is 0–3 mg/kg of body weight (JECFA, 2004;
EFSA, 2014). Several investigations have reported that this compound
is safe in humans, and its broad range of therapeutic activity has been
observed at different doses for different diseases with negligible tox-
icity (Clinical development plan, 1996; National Toxicology Program,
1992). Initial studies conducted to determine the safe and tolerable
dosage of curcumin revealed that this compound was well-tolerated
up to a dose of 8,000 mg/day in humans (Cheng et al., 2001; Deodhar
et al., 1980; Satoskar, Shah, & Shenoy, 1986; Soni & Kuttan, 1992).
However, in 2006, Lao et al. reported that healthy people could toler-
ate curcumin up to 12,000 mg/day without any adverse side effects
(Lao et al., 2006). In healthy subjects, curcumin has been found to
exert cholekinetic activity and induce cardio protection (Rasyid
et al., 2002; Rasyid & Lelo, 1999; Sugawara et al., 2012). Assessment
of pharmacokinetic properties of curcumin after 72 hr of administra-
tion in a healthy group revealed that it was converted into glucuronide
and sulfate conjugates that could be detected in the plasma (Vareed
et al., 2008). The reduction of serum cholesterol and triglyceride levels
was also evident after curcumin treatment in healthy humans
(Pungcharoenkul & Thongnopnua, 2011). In addition, curcumin
remarkably reduced triglyceride, β amyloid, soluble intercellular adhe-
sion molecule, ALT levels in plasma, and amylase levels in the saliva of
healthy middle-aged volunteers. At the same time, it enhanced radical
scavenging activity in the saliva of these volunteers and the activities
of catalase and myeloperoxidase (MPO) in their plasma, without
affecting the amount of CRP or plasma nitric oxide (NO) (DiSilvestro
et al., 2012). Curcumin was also found to reduce oxidative stress in
healthy individuals when combined with epigallocatechin gallate, res-
veratrol, and soya bean extract (Dominiak et al., 2010). The combina-
tion of curcumin with piperine was also administered to healthy
individuals, and a significant increase in bioavailability was observed
without any adverse effects (Shoba et al., 1998). However, the combi-
nation of curcumin and talinolol negatively impacted the bioavailabil-
ity of curcumin (Juan et al., 2007). To overcome poor bioavailability
and promote the efficacious use of curcumin, studies have been car-
ried out with its several novel formulations such as nano curcumin,
Meriva®, nano-encapsulation with hydrophilic carriers, and these for-
mulations have been found to be well-tolerated with enhanced pro-
tective effect (Cuomo et al., 2011; Jäger et al., 2014; Saadipoor
et al., 2019). Overall, these studies implicate that curcumin is safe,
effective, and well-tolerated, and it can be used in the prevention and
treatment of various chronic diseases.
3.2 | Curcumin for cancers
Like other chronic diseases, cancer contributes to a significant per-
centage of mortality worldwide every year, despite the advancement
in treatment modalities (Girisa, Parama, Harsha, Banik, &
Kunnumakkara, 2020; Kumar, Golani, & Kumar, 2020; Monisha
et al., 2018; Padmavathi et al., 2015; Roy et al., 2016; Tang, Sethi, &
Kuo, 2014). The prime etiological factors of this disease are unhealthy
lifestyle and diet, consumption of alcohol, tobacco, genetic predisposi-
tion, exposure to ultraviolet light, infection with viruses, etc. (Anand
et al., 2008; Banik et al., 2019; Dai et al., 2015; Girisa et al., 2019;
Henamayee et al., 2020; Kunnumakkara, Bordoloi, et al., 2019; Sailo
et al., 2018; Sailo et al., 2019; Shabnam et al., 2018). A plethora of
studies have illuminated the anticancer potential of curcumin over the
past decades. In addition to innumerable preclinical studies, several
clinical investigations have been conducted, and many are underway
TABLE 1 Curcumin clinical trials in patients with various chronic diseases

Disease Curcumin dose Pts (#) Clinical outcome References

Safety and tolerability
KUMAR ET AL.

Healthy volunteers 2 ga,b 10 Safe and highly bioavailable Shoba et al. (1998)
20 mgb 12 Safe and induced gall-bladder contraction Rasyid and Lelo (1999)
b
20 mg, 40 mg, 80 mg 12 Safe and increased gall-bladder contraction Rasyid, Rahman, Jaalam, and Lelo (2002)
0.5 g; 2 daysc 10 Safe and no effect on iron absorption Tuntipopipat et al. (2006)
b
500–12,000 mg 24 Safe and well-tolerated Lao et al. (2006)
300 mg/day; 6 daysa 12 Safe Juan et al. (2007)
b
10 g,12 g 12 Safe and improved absorption Vareed et al. (2008)
500 mga,c,b 8 Safe and activated bowel motility Shimouchi, Nose, Takaoka, Hayashi, and Kondo (2009)
150 mg/day; 2 weeksa 11 Safe and well-tolerated Dominiak, McKinney, Heilbrun, and Sarkar (2010)
0.5,6 g/day; 7 days 24 Safe and decreased lipid levels Pungcharoenkul and Thongnopnua (2011)
30 mgb,d 14 Safe and bioavailable Sasaki et al. (2011)
3  209–376 mg/dayd 9 Safe and improved absorption Cuomo et al. (2011)
80 mg/day; 4 weeks 38 Safe and have multiple health benefits DiSilvestro, Joseph, Zhao, and Bomser (2012)
150 mg/day; 8 weeks 45 Safe and improved BP and heart rate Sugawara et al. (2012)
1 g/100 g portiona ,b ,d 10 Safe and bioavailable Vitaglione et al. (2012)
2 ga,b 8 Safe and bioavailable Kusuhara et al. (2012)
a
4  4 g; 2 days 8 Safe and highly bioavailable Volak et al. (2013)
376 mgb,d 15 Safe and bioavailable Jäger et al. (2014)
b,d
12 g 10 Safe and well-tolerated Klickovic et al. (2014)
500 mgb 23 Safe and highly bioavailable Schiborr et al. (2014)
10–400 mg/m2d 50 Safe and well-tolerated Storka et al. (2015)
98 mgb ,d 23 Safe and bioavailable Kocher, Schiborr, Behnam, and Frank (2015)
2 g, 4 ga ,d 12 Safe and bioavailable Asher et al. (2017)
Cancer
BPH 1 g/day; 24 weeksa 61 Reduced signs and symptoms Ledda et al. (2012)
Breast 6 g/day; 7 daysa 14 Safe and well-tolerated Bayet-Robert et al. (2010)
Cancerous lesions Ointment 62 Reduced lesion size and pain Kuttan, Sudheeran, and Josph (1987)
0.5–1.2 g/day; 3 months 25 Well-tolerated and efficacious Cheng et al. (2001)
a,d
Cervical 500 mg/day; 30 days 280 Increased HPV clearance rate Basu et al. (2013)
CML 3  5 g; 6 weeksc 50 Reduced nitric oxide levels Ghalaut et al. (2012)
d
Colorectal 0.44–2.2 g/day; 29 days 15 Inhibited basal and LPS-induced PGE2 Plummer et al. (2001)
0.44–2.2 g/dayc ,d; 4 months 15 Well-tolerated Sharma et al. (2001)
c,d
0.45- 3.6 g/day; 4 months 15 Well-tolerated and efficacious Sharma et al. (2004)
5

(Continues)
 6

TABLE 1 (Continued)

Disease Curcumin dose Pts (#) Clinical outcome References

0.45 mg, 1.8 mg, 3.6 mg/day; 7 days 12 Inhibited inflammation and DNA damage Garcea et al. (2005)
1.08 g/day; 10–30 daysb 26 Improved the general health He et al. (2011)
2 or 4 g/day; 30 days 44 40% reduction in ACF number Carroll et al. (2011)
a,c
2.35 g/day; 14 days 26 High levels of curcumin were recovered Irving et al. (2013)
3 g/day; 1 yeara 44 No significant effect Cruz-Correa et al. (2018)
d
2 g/weeks; 12 weeks 28 Safe and well-tolerated Howells et al. (2019)
HNSCC 1 gb 39 Decreased IKKβ kinase activity in saliva S. G. Kim et al. (2011)
Pancreatic 8 g/day; 8 weeks 25 Safe, well-tolerated, and efficacious Dhillon et al. (2008)
8 g/day; 4 weeksa 17 Showed partial response and stable disease Epelbaum, Schaffer, Vizel, Badmaev, and Bar-Sela (2010)
a
8 g/day; 14 days every 3 weeks 21 Safe and well-tolerated Kanai et al. (2011)
0.2 g–0.4 g/day; 9 months 16 Safe and well-tolerated Kanai et al. (2013)
Prostate 100 mg/day; 6 monthsa 85 Reduced serum PSA levels Ide et al. (2010)
3 g/day; 3 months 40 No significant effect Hejazi et al. (2016)
d
Solid tumors 3  100 mg/day; 4 months 160 Decreased side effects of chemotherapy Belcaro et al. (2014)
180 mg/day; 8 weeks 80 Improved quality of life Panahi, Saadat, Beiraghdar, and Sahebkar (2014)
Cardiovascular disease
ACS 45–180 mg/day; 2 months 75 Reduced total cholesterol and LDL cholesterol Alwi et al. (2008)
AMI 4 g/day; 7 days 121 Inhibited MI associated with CABG Wongcharoen et al. (2012)
CVH 4.5 gc,b 14 Improves postprandial endothelial function Nakayama et al. (2014)
Dyslipidemia 1 g/day; 30 days 30 Decreased triglycerides level Mohammadi et al. (2013)
Metabolic and CVH 0.9 g/day; 24 weeksa 56 No effect Soare, Weiss, Holloszy, and Fontana (2014)
MS 1,890 mg/day; 12 weeks 65 Lowered lipid level Yang et al. (2014)
1,000 mg/day; 8 weeksa 100 Effective as adjunctive therapy Panahi, Khalili, Hosseini, Abbasinazari, and Sahebkar (2014)
294 mg/day; 6 weeks 42 Safe and well-tolerated Kocher, Bohnert, Schiborr, and Frank (2016)
Inflammatory diseases
Bronchial asthma 1 g/day; 30 days 77 Decreased airway obstruction Abidi, Gupta, Agarwal, Bhalla, and Saluja (2014)
CKD 2  824 mg/day; 8 weeksa 16 Safe and well-tolerated Moreillon et al. (2013)
90 mg/day; 6 months 500 Safe and well-tolerated Weir et al. (2018)
2.5 g/week; 3 monthsc ,d 31 Decreased inflammatory markers Alvarenga et al. (2020)
Crohn's disease 1.1 g and 1.6 g/day; 2 months 5 Efficacious Holt, Katz, and Kirshoff (2005)
FAP 3  480 mg/day; 6 monthsa 5 Decreased number and size of adenomas Cruz-Correa et al. (2006)
3,000 mg/day; 12 months 44 No significant effect Cruz-Correa et al. (2018)
Gastritis 3  700 mg/day; 4 weeksc 36 No significant effect Koosirirat, Linpisarn, Changsom, Chawansuntati, and
Wipasa (2010)
KUMAR ET AL.
TABLE 1 (Continued)
Disease Curcumin dose
Gingivitis Mouthwash
Helicobacter pylori infection 2  30 mg/day; 7 days
IBD 1–4 g/day; 9 weeks
Nephritis 500 mg/day; 3 months
OLP 2,000 mg/day; 7 weeks
6,000 mg/day
Oral mucositis 2  10 drops/dayd; 21 days
With honeya,c
Osteoarthritis 1 g/dayd
200 mgd
1,000 mg/day; 3 months
1,500 mg/day; 4 weeks
1,500 mg/day; 6 weeks
180 mg/day; 8 weeksd
2  126 mg/day; 3 months
2  3 caps/day; 3 monthsd
a
Pancreatitis 0.5 g/day; 6 weeks
Peptic ulcer 3 g/day; 4–12 weeksc
Periodontitis 2% gelc
1%/solution; 3 weeksd
d
1% gel; 1, 3, and 6 months
50 mg/cm2; 6 monthsd
Plaque 2  0.1%; 21 daysc
Prostatitis 200 mg/day; 14 daysa
Pulmonary complication 500 mg; 4 weeks
Rheumatoid arthritis 1.2 g/day; 2 weeks
a
2  500 mg/day; 8 weeks
Ulcerative colitis 2 g/day; 6 months
0.5 g/day; 1 year
140 mg/day; 8 weeksa,d
a
3 g/day; 1 month
Ulcerative proctitis 1.1 g and 1.65 g/day; 1 month
Pts (#) Clinical outcome References
30 Effective in mechanical periodontal therapy Muglikar, Patil, Shivswami, and Hegde (2013)
KUMAR ET AL.
25 Improved dyspeptic symptoms Di Mario et al. (2007)
11 Significant decrease in relapse Suskind et al. (2013)
24 Decreased proteinuria, hematuria, and BP Khajehdehi et al. (2012)
33 Safe and well-tolerated Chainani-Wu et al. (2007)
20 Safe, well-tolerated, and efficacious Chainani-Wu, Madden, Lozada-Nur, and Silverman Jr. (2012)
7 Well-tolerated and efficacious Elad et al. (2013)
60 Inhibited oral mucositis Francis and Williams (2014)
100 Safe and efficacious Belcaro et al. (2010a)
50 Efficacious Belcaro et al. (2010b)
44 Served as adjuvant therapy Pinsornsak and Niempoog (2012)
367 As effective as ibuprofen Kuptniratsaikul et al. (2014)
40 Safe and efficacious Panahi, Rahimnia, et al. (2014)
50 Efficacious Nakagawa et al. (2014)
22 Significant improvement Henrotin et al. (2014)
150 Reduction in disease activity Henrotin et al. (2019)
20 Reduced MDA and increased GSH Durgaprasad, Pai, Vasanthkumar, Alvres, and Namitha (2005)
45 Subsided abdominal pain and discomfort Prucksunand, Indrasukhsri, Leethochawalit, and
Hungspreugs (2001)
30 Effective in scaling and root planing Behal, Mali, Gilda, and Paradkar (2011)
23 Mild to moderate beneficiary effect Gottumukkala, Koneru, Mannem, and Mandalapu (2013)
25 Inhibited growth of oral bacteria Bhatia, Urolagin, Pentyala, Urolagin, and Bhoi (2014)
60 Reduced plaque and gingival index scores Gottumukkala, Sudarshan, and Mantena (2014)
100 Prevented plaque and gingivitis Waghmare, Chaudhari, Karhadkar, and Jamkhande (2011)
284 Improved efficacy of prulifloxacin Cai et al. (2009)
89 Safe, well-tolerated, and efficacious Panahi, Ghanei, Bashiri, Hajihashemi, and Sahebkar (2015)
18 Reduced stiffness and joint swelling Deodhar, Sethi, and Srimal (1980)
45 Reduced DAS and ACR scores Chandran and Goel (2012)
45 Prevented disease relapse Hanai et al. (2006)
1 Efficacious Lahiff and Moss (2011)
45 Safe and efficacious Singla et al. (2014)
50 Effective, no adverse effects Lang et al. (2015)
5 Efficacious Holt et al. (2005)
7
(Continues)

TABLE 1 (Continued)
Disease Curcumin dose
Uveitis 1.125 g/day; 12 weeks
2  0.6 g/day; 12–18 months
Metabolic disease
Diabetes 5 g/day; 3 months
600 mg/day; 8 weeks
c
3  500 mg/day; 2 months
1.5 g/day; 3, 6 and 9 months
300 mg/day; 3 months
2  750 mg/day; 6 months
500 mg/day; 15–30 days
d
1 g/day; 4 weeks
1 g/day; 4 weeksd
2 cap/day; 6 months
Obesity 1 g/day; 30 days
1 g/day; 4 weeks
1 g/day; 30 days
Neurological disease
Alzheimer's disease 2 g and 4 g/day; 24 weeks
1 g and 4 g/day; 6 months
2 g and 4 g/day; 24 weeks
Depression 500 mg/day; 5 weeks
1 g/day; 8 weeks
1,000 mg/day; 6 weeks
10–1,000 mg/day; 6 weeksa
2  0.5 g/day; 8 weeks
2  1 g/day; 6 weeks
Schizophrenia 3 g/day; 6 months
360 mg/day
Skin diseases
Psoriasis 2  1%/day; 4 weeks
d
4.5 g/day; 16 weeks
2 g/day; 12 weeks
8
Pts (#) Clinical outcome References
53 Efficacy equal to corticosteroid therapy Lal et al. (1999)
122 Well-tolerated and reduced eye discomfort Allegri, Mastromarino, and Neri (2010)
1 Decreased fasting blood sugar level Srinivasan (1972)
72 Inhibited cytokines and oxidative stress Usharani, Mateen, Naidu, Raju, and Chandra (2008)
40 Attenuated proteinuria, TGF-β, and IL-8 Khajehdehi et al. (2011)
240 Safe, well-tolerated, and efficacious Chuengsamarn, Rattanamongkolgul, Luechapudiporn,
Phisalaphong, and Jirawatnotai (2012)
100 Decreased serum A-FABP level Na et al. (2014)
240 Lowered the atherogenic risks Chuengsamarn, Rattanamongkolgul, Phonrat, Tungtrongchitr,
and Jirawatnotai (2014)
— Reduced albumin excretion, activated Nrf2 Yang et al. (2015)
25 Decreased edema score, improved response Appendino et al. (2011)
38 Efficacious Steigerwalt et al. (2012)
67 Effective, improved serum lipids Chous, Richer, Gerson, and Kowluru (2016)
30 Decreased oxidative stress Mohammadi et al. (2013)
30 Improved immune response Ganjali et al. (2014)
30 Reduced anxiety Esmaily et al. (2015)
33 Patients' responses yet to be published Ringman, Frautschy, Cole, Masterman, and Cummings (2005)
34 Safe and increased vitamin E level Baum et al. (2008)
36 Safe and efficacious, no significant change Ringman et al. (2012)
40 Reduced symptoms Bergman et al. (2013)
56 Reduced depression Lopresti, Maes, Maker, Hood, and Drummond (2014)
60 Safe and efficacious Sanmukhani et al. (2014)
111 Safe and efficacious Panahi, Badeli, Karami, and Sahebkar (2015)
50 Reduced IDS-SR30 score Lopresti et al. (2015)
108 Reduced depression Yu, Pei, Zhang, Wen, and Yang (2015)
38 Safe and efficacious Miodownik et al. (2019)
45 Increased BDNF levels Wynn et al. (2018)
40 Suppressed PhK activity Heng, Song, Harker, and Heng (2000)
12 Showed response rate 16.7% Kurd et al. (2008)
63 Effective and decreased serum IL-22 levels Antiga, Bonciolini, Volpi, Del Bianco, and Caproni (2015)
KUMAR ET AL.
TABLE 1 (Continued)

Disease Curcumin dose Pts (#) Clinical outcome References

Radiation dermatitis 6 g/day throughout RT 30 Reduced severity of radiation Ryan et al. (2013)
KUMAR ET AL.

Vitiligo 2  cream/week; 12 weeks 10 Improved degree of repigmentation Asawanonda and Klahan (2010)
Infectious diseases
HIV 2.5 g/day; 56 days 40 Well-tolerated James (1996)
Tuberculosis 6 g/day; 2–4 monthsd 528 Prevented hepatotoxicity Adhvaryu, Reddy, and Vakharia (2008)
Others
AAA 4 g/day; 4 days 606 No significant effect Garg et al. (2018)
a
Arsenic carcinogenicity 2  500 mg/day; 3 months 286 Reduced DNA damage Biswas et al. (2010)
Cholecystectomy 500 mg/every 6 hr 50 Improved postoperative pain Agarwal, Tripathi, Agarwal, and Saluja (2011)
a
CRT 480 mg/day; 1 month 43 Improved graft function, reduced rejection Shoskes et al. (2005)
Déjérine–Sottas 50–75 mg/kg/day; 12 months 1 Improved patients' quality of life Burns, Joseph, Rose, Ryan, and Ouvrier (2009)
MGUS and SMM 2  2 g/day; 3 months 36 Slowed the disease process Golombick, Diamond, Manoharan, and Ramakrishna (2012)
MGUS 2  2 g/day; 6 months 26 Reduced paraprotein levels Golombick, Diamond, Badmaev, Manoharan, and
Ramakrishna (2009)
Oxidative stress 90 mgb 10 Reduced oxidative stress Takahashi et al. (2014)
PMS 2 capsules/day; 7 days 70 Attenuated severity of PMS symptoms Khayat et al. (2015)
Pruritus 1 g/day; 4 weeks 96 Safe, effective and anti-inflammatory Panahi, Sahebkar, Amiri, et al. (2012)
Thalassemia 500 mg/day; 12 months 21 Ameliorated oxidative damage Kalpravidh et al. (2010)
Vascular reactivity 5 g/day; 2 hrd 18 Increased flow-mediated dilation Barber-Chamoux et al. (2018)
VEF 150 mg/day; 8 weeks 32 Improved endothelial function Akazawa et al. (2012)

Abbreviations: A-FABP, adipocyte fatty acid binding protein; AAA, abdominal aortic aneurysm; AC, arsenic carcinogenicity; ACR, American College of Rheumatology; ACS, acute coronary syndrome; AMI, acute
myocardial infarction; BP, blood pressure; BPH, benign prostatic hyperplasia; CABG, coronary artery bypass graft; CBP, chronic bacterial prostatitis; CDAI, clinical disease activity index; CKD, chronic kidney
disease; CML, chronic myeloid leukemia; CP, chronic periodontitis; CRT, cadaveric renal transplantation; CVH, cardiovascular health; DAS, disease activity score; DM, diabetic microangiopathy; DR, diabetic
retinopathy; FAP, familial adenomatous polyposis; GSH, glutathione; HC, hepatocellular carcinoma; HM, haematological malignancies; HNSCC, head and neck squamous cell carcinoma; IBD, inflammatory bowel
disease; LN, lupus nephritis; MDA, malonaldialdehyde; MDD, major depressive disorder; MGUS, monoclonal gammopathy of undetermined significance; MI, myocardial infarction; MS, metabolic syndrome; OLP,
oral lichen planus; PGE2, prostaglandin E2; PMS, premenstrual syndrome; PSA, prostate-specific antigen; SMM, smoldering multiple myeloma; T2D, type 2 diabetes; THC, tetrahydrocurcuminoid; UC, ulcerative
colitis; VEF, vascular endothelial function.
a
Combination.
b
Administered once.
c
Turmeric.
d
Curcumin formulation.
9
 Ongoing clinical trials of curcumin for various chronic diseases in humans
10

TABLE 2

Disease ID Dose Phase Affiliation Start date Clinical trials

Safety and tolerability
Healthy individuals 4 ga — Michael Seiden; MGH, United States August 2005 NCT00181662
2,000 mg/day; 14 daysb I Lisa Flowers; Emory University January 2010 NCT01035580
b
NA I Tetyana Pelipyagina; KGK Synergize April 2015 NCT02474953
990 mg/day; 4 weeksb — Hang Xiao; UM, Amherst December 2018 NCT03746158
a,b
400 mg — Melanie Plourde; Université de Sherbrooke June 2020 NCT04382014
1,200 mg/day; 2 weeks I Michael A Liss; UT San Antonio September 2020 NCT04421716
Cancer
Breast cancer 50 mg and 100 mg; 3 months — Steven Clinton; OSU, United States June 2013 NCT01975363
1000 mg II Andrew Mille; Emory University, US May 2015 NCT01740323
300 mg/weeks; 12 weeksb II Armen Tananyan; NCO, Armenia March 2017 NCT03072992
a
8 g/day — Nur Aishah; University of Malaya June 2017 NCT03847623
Curcumin supplement — Juan C. Espín; NRC, Spain June 2017 NCT03482401
Curcumin supplement — Lisa D Yee; City of Hope Medical Center March 2019 NCT03865992
1,000 mg/day I Nancy DeMore; MU of South Carolina January 2020 NCT03980509
Cancer 200 mg/day; 28 days I David Hong; MDACC United States October 2011 NCT01201694
100–300 mg/m2; 8 weeksb I/II Richard Greil; Internistische Onkologie March 2014 NCT02138955
CIN 1,000 mg/day; 12 weeks 0 Carolyn Matthews; Texas Oncology March 2016 NCT02554344
2,000 mg/week; 12 weeksa,b II Lisa Flowers; Emory University November 2017 NCT02944578
a
2,000 mg/day II Jose A Carreño; INDC, Columbia June 2020 NCT04294836
2,000 mg/week; 20 weeksa,b II Lisa Flowers; Emory University August 2020 NCT04266275
a
Colon cancer NA I Dean E. Brenner; University of Michigan December 2001 NCT00027495
NAa III Arie Figer; TASMC, Israel March 2006 NCT00295035
b
Curcumin supplement I William Steward; UHL, United Kingdom July 2009 NCT00973869
4 g/day; 30 daysb I Gary Asher; UNC-CH, United States November 2010 NCT01333917
a
3.6 g/day; 7 days I Donald Miller; JGBCC, United States January 2011 NCT01294072
1–4 g/day; 4 daysa I Gary Asher; UNC-CH, United States June 2013 NCT01859858
a,b
0.5, 1 g/day; 28 days Andrea DeCensi; EO, Ospedali Galliera March 2014 NCT01948661
200 mg/daya II Jeong-Heum Baek; Gachon University August 2015 NCT02439385
1,000 mg/day; 2 weeksa Early I John Preskitt; Texas Oncology, PA March 2016 NCT02724202
200 mg/dayb II Revital Kariv; Tel Aviv SMC April 2017 NCT03061591
Glioblastoma NA _ Stephan Duetzmann; GU, Germany October 2012 NCT01712542
H&NC 8 g/day; 21–28 days Early I Cherie-Ann Nathan; LSUHSC, United States June 2010 NCT01160302
4,000 mg/day; 60 days II Tawasapon Thambamroong; PH, Thailand February 2020 NCT04208334
KUMAR ET AL.
TABLE 2 (Continued)

Disease ID Dose Phase Affiliation Start date Clinical trials

Lymphoma NAa II Paolo Caimi Case; CCC, United States September 2014 NCT02100423
KUMAR ET AL.

Multiple myeloma 22g — Saroj Vadhan-Raj; MDACC, United States November 2004 NCT00113841
Osteosarcoma Curcumin powder I/II Manish Agarwal; TMH, India May 2008 NCT00689195
NSCLC 80 mg/day; 8 weeksa,b I Victor Cohen; LDI, Canada August 2015 NCT02321293
2–4 g/dayb II Nagi Kumar, HLMCC, United States June 2019 NCT03598309
Pancreatic cancer 8 g/day; 8 weeks II Vivek Subbiah; MDACC, United States November 2004 NCT00094445
NAa III Arber Nadir; TAU, Israel June 2005 NCT00486460
b
Curcumin supplement I Vincent Chung; CHMC, United States January 2016 NCT02336087
Prostate cancer 3 g/day; 8 weeksa — Reza Rastmanesh; Shahid Beheshti U March 2011 NCT01917890
a
NA II Centre Jean Perrin March 2014 NCT02095717
1,000 mg/day III Yair Lotan; UTS Medical Center May 2014 NCT02064673
120 mg/daya,b II Abolfazl Razzaghdoust; SBUMS, Iran March 2016 NCT02724618
1,000 mg/dayb ,c — David Levy; CCCC, United States September 2017 NCT03290417
1,000 mg/dayb III Yair Lotan; UTS Medical Center March 2019 NCT03769766
1,200 mg/day Early I Michael A Liss; UT San Antonio September 2020 NCT04403568
Rectal cancer 8 g/daya II Sunil Krishnan; MDACC, United States August 2008 NCT00745134
Uterine cancer 2 g/day; 2 weeksb II Frederic Amant; UZ Leuven October 2013 NCT02017353
b
Curcumin supplement I Aminah Jatoi; Mayo Clinic March 2016 NCT02598726
Curcumin supplementb II Hannelore Denys; UH, Ghent July 2017 NCT03192059
Cardiovascular disease
CAD 200 mg/day; 7 daysa II Mark Sarzynski, CCRC, Columbia September 2016 NCT02998918
b
1,500 mg/day, 4 weeks — Denise Mafra; UFF, Brazil November 2020 NCT04458116
CVD NAb — Anwar Tandar; University of Utah, United States June 2013 NCT02088307
Microvascular response 10 g powder/day — Cristina Rezende; UFRJ-Campus Macaé January 2019 NCT04119752
MS 1.2 g/day; 3 monthsc — Fernando Guerrero; IMDSS, Mexico May 2018 NCT03795792
b
NA — Azita Hekmatdoost; NNFTI, Iran August 2018 NCT03534024
Inflammatory diseases
Atopic asthma 2g — Richard Lockey; USF, United States March 2009 NCT01179256
3g II Laren Tan; Loma Linda University September 2021 NCT04353310
d
Acute pulpitis 400 mg — Mohamed Sobhy; Cairo University August 2019 NCT04012424
Atrophic gastritis NAb II Marcia R Cruz-Correa; Mayo Clinic April 2017 NCT02782949
RA 1–2  4 cap/day; 2 weeks 0 Dinesh Khanna;UC, United States January 2010 NCT00752154
Crohn's disease 3 g/day; 6 monthsa III Gilles Bommelaer; UCF, France December 2014 NCT02255370
b
NA — Zhaoping Li; UC, LA, United States October 2020 NCT04431700
11

(Continues)
 (Continued)
12

TABLE 2

Disease ID Dose Phase Affiliation Start date Clinical trials

CKD NAc; 8 weeks III Magdalena Madero; INDCIC, Mexico February 2013 NCT01831193
d
2,000 mg II Diana Jalal; University of Iowa January 2018 NCT03223883
800 mg/daya II/III Unidad de Investigacion Medica, Mexico August 2018 NCT03262363
d
2,000 mg II Nicholas Kruse; University of Iowa November 2020 NCT04132648
1,500 mg/day; 12 weeks — Denise Mafra; UFF, Brazil October 2020 NCT04413266
a
Helicobacter pylori infection NA — Gingold Rachel; RMC, Israel January 2014 NCT02018328
IBD 4 g/day; 1 yearb — Henit Yanai; RMC, Israel June 2020 NCT03500653
b
NA — Carlo Catassi; UPDM, Italy December 2019 NCT04513015
Bowel syndrome 1,800 mg/day IV Chris N Conteas; KP, United States November 2008 NCT00779493
500 mg; 4 weeksb II Timna Naftali; TAU, Isreal April 2011 NCT01167673
50 mg  2/dayb — Manu Sood; Medical College Wisconsin August 2018 NCT03568513
COPD NAa — Sharafkhaneh; BCM, United States April 2005 NCT01514266
Cystitis NAb II Massimo LAzzeri; GDSM, Urogenitali April 2017 NCT03493997
Mucositis 0.33–3 g/day; 4–6 weeks I and II Dhimant Patel; ABMC, United States February 2015 NCT02300727
OAU Curcumin gela — Mahin Bakhshi; SBUMC, Iran July 2018 NCT04385979
a
OLP Curcumin gel I Mohamed salah abd-elhameed, CU, Egypt May 2019 NCT03877679
OSMF Curcumin gel II SVSIDS; India December 2013 NCT02645656
Orthodontics Mouthwasha I Vitor H Panho

ca; USP, Brazil January 2014 NCT02337192
Osteoarthritis NAb — Ivan Shirinsky;RIFCI, United States June 2018 NCT03540186
2  1 tab/day; 6 weeksb — Massimo Frascarello; ISS, Italy December 2019 NCT04207021
UC 1 g/day; 2 months — Iris Dotan; TASMC, Israel November 2008 NCT00793130
Curcumin capsules III Amit Assa; SCMCI, Israel March 2020 NCT02277223
100-200 mg; 2 weeksa III Rupa Banerjee; AIG, India February 2016 NCT02683759
b ,c
3 g/day — Siew Chien; CU of Hong Kong June 2017 NCT03122613
2-4 g/dayb III Amit Assa, SCMCI, Israel March 2020 NCT02277223
Periodontitis Curcumin gelc IV Dhanashree Agarwal, TKDC, India January 2014 NCT02442453
Curcumin pastea,b,d IV Ahmed Y Gamal; Ain shams University August 2016 NCT04044417
a
Curcumin paste IV Ahmed Y Gamal; Ain shams University August 2016 NCT04032132
1% curcumin chips III Riya Daniel; KLE Society's IDS, Bangalore September 2019 NCT03790605
a
Curcumin gel Early I Haider Thabit; University of Baghdad April 2020 NCT04355416
PIDE Curcumin supplement — Meir Medical Center January 2017 NCT03016039
PSC 1000 mg; 12 weeksb I/II John E. Eaton; Mayo Clinic June 2017 NCT02978339
KUMAR ET AL.
TABLE 2 (Continued)

Disease ID Dose Phase Affiliation Start date Clinical trials

Metabolic disease
KUMAR ET AL.

Diabetes 500 mg II/III NNFTRI, Iran July 2015 NCT02529969

500 mg NNFTRI, Iran July 2015 NCT02529982
b
NA — Sandip Patil; MCIM, India September 2015 NCT02834078
1,500 mg/day; 12 weeks II/III Azita Hekmatdoost; NNFTRI, Iran February 2017 NCT02908152
1,000 mg/day; 3 months IV HGD México Dr. Eduardo Liceaga February 2019 NCT03917784
DR NAb I Robert Ritch; NYEI, New York April 2016 NCT02984813
b
NA — Ciro Costagliola; University of Molise September 2019 NCT04378972
Obesity 600 mg/day; 3 monthsb — Fernando Romero; CDIES, Mexico January 2018 NCT03670875
b
500 mg/day — Susan Wolver; VCU, United States September 2018 NCT03542240
200 mg/day; 42 daysb — Pernille H Hellmann; CCMR, Denmark March 2019 NCT03864783
Neurological disease
Alzheimer's disease 4 g or 6 g/day II Fali Poncha; JHRC, India October 2009 NCT01001637
b
25 mg/week for 6 weeks I Paul Wand; LEFI February 2010 NCT01716637
800 mg/6 monthsa I Sally Frautschy; VAORD, United States January 2014 NCT01811381
Depression 1000 mg/day ; 6 weeksa — Bharat Panchal; GMC, India March 2009 NCT01022632
500 mg/day; 6 weeks IV Joseph Bergman; Tirat Carmel August 2010 NCT01750359
Cognitive function 1,000 mg/day II/III Stephen D Anton; University of Florida August 2017 NCT03085680
MCI 180 mg/day; 18 monthsb II Gary W Small; UCLA Longevity Center March 2012 NCT01383161
b
Schizophrenia 1 or 4 g/day; 16 weeks I/II Woodbury Michel; LHRI, Canada June 2009 NCT01875822
Skin disease
Psoriasis NAb II Joel Gelfand; UPENN, United States October 2005 NCT00235625
4/day; 28 daysb I Elorac, Inc. United States September 2014 NCT02251678
Curcumin gelc II/III Hagar Nofal; Zagazig University September 2019 NCT04071106
Radiation dermatitis 2 g/dayb II Julie Ryan; University of Rochester January 2008 NCT01042938
1500 mg/dayb II/III Julie Ryan; University of Rochester February 2011 NCT01246973
Curcumin gelb II Gary Morrow; University of Rochester October 2015 NCT02556632
Other
ACF 2 g and 4 g/day; 30 days II Frank Meyskens; CFCCC, United States October 2006 NCT00365209
ADPKD 25 mg/kg/day; 1 year IV Kristen Nowak; CU, United States November 2015 NCT02494141
CSH 810 mg/dayb,d Early I Howard Yonas; UNM, Mexico December 2018 NCT03845322
Cystic fibrosis 4.5 g and 9 g/day; 7 days I Chris Goss; UW, United States April 2005 NCT00219882
COVID19 20 mg/mla,b; 2 weeks II Rubi Zomer; MGC Pharmaceuticals May 2020 NCT04382040
EDN 800 mg/dayb II/III Laura Cortes-Sanabria; UHDE, Brazil August 2018 NCT03262363
13

(Continues)
 (Continued)
14

TABLE 2

Disease ID Dose Phase Affiliation Start date Clinical trials

Erectile dysfunction 12 g/day; 8 weeksb IV Hyun Jun Park; PNUH, South Korea February 2012 NCT02413099
c
ESRD 1500 mg/day; 8 weeks I/II SUMS, Iran April 2011 NCT01906840
Fibromyalgia 5 weeksb — Grégoire Cozon; HCL, France November 2011 NCT01469936
HTA NAa — Mazen A Hanna; The Cleveland Clinic February 2018 NCT03431896
Hyper prolactinoma NA I Mashhad University of Medical Sciences July 2011 NCT01344291
Kidney allografts 2 ml of 12/mg/mla,b I Kaija Salmela; HUCH, Finland January 2011 NCT01285375
LHON 500 mg/day III Wanicha Chuenkongkaew; MU, Thailand May 2005 NCT00528151
Migraine 4 g/day; 2 months IV TUMS, Iran September 2015 NCT02532023
Multiple sclerosis 1 g/day II Merck KGaA; Germany April 2012 NCT01514370
80 mg/day; 6 monthsa II Mehdi Yousefi; TUMS, Iran June 2016 NCT03150966
NAFLD NAb — Giovanni de Gaetano; Neuromed IRCCS August 2015 NCT02369536
500–1,000 mg/day; 24 weeksb II Elena Reynoso; Columbia University October 2019 NCT04109742
Prostatectomy 1 g/day; 6 months III Yair Lotan; UTSW, United States May 2014 NCT02064673
Proteinuria NA III Magdalena Madero; INDCIC, Mexico February 2013 NCT01831193
1.67 g/day; 6 monthsb II Magdalena Madero; INDCIC, Mexico May 2016 NCT03019848
b
SLE 2 g/day II Vaneet Sandhu, Loma Linda University September 2019 NCT03953261
Vascular aging 500–2,000 mg/day — Douglas Seals; CU, United States June 2013 NCT01968564
Vascular stiffness 200 mg/7 days I Jamie Burr; UPEI, Canada November 2014 NCT02281981

Abbreviations: ACF, aberrant crypt foci; ADH, atypical ductal hyperplasia; ADPKD, autosomal dominant polycystic kidney disease; CAD, coronary artery disease; CIN, cervical intraepithelial neoplasia; CKD,
chronic kidney disease; COPD, chronic obstructive pulmonary disease; COVID19, novel coronavirus 2019; CP, chronic periodontitis; CSH, chronic subdural hematomas; CVD, cardiovascular disease; DR, diabetic
retinopathy; EC, endometrial carcinoma; EDN, early diabetic neuropathy; ESRD, end-stage kidney disease; FAP, familial adenomatous polyposis; H&NC, head and neck cancer; HTA, hereditary transthyretin
amyloidosis; IBD, inflammatory bowel disease; LHON, Leber's hereditary optic neuropathy; MCI, mild cognitive impairment; MDS, myelodysplastic syndrome; MS, metabolic syndrome; NA, not available; NAFLD,
non-alcoholic fatty liver disease; NSCLC, non-small cell lung cancer; OAU, oral aphthous ulcer; OLP, oral lichen planus; OSMF, oral submucous fibrosis; PIDE, pelvic inflammatory disease endometritis; RA,
rheumatoid arthritis; SLE, systemic lupus erythematosus; T2D, type 2 diabetes; UC, ulcerative colitis.
a
Combination.
b
Curcumin formulation.
c
Turmeric.
d
Administered once.
KUMAR ET AL.
KUMAR ET AL.
to validate the safety and efficacy of this golden nutraceutical. In
2001, a phase I study reported remarkable histologic improvement of
premalignant lesions in patients with recently resected bladder cancer
(50%), leukoplakia (28.6%), intestinal metaplasia of the stomach
(16.6%), uterine cervical intraepithelial neoplasm (25%), and Bowen's
disease (33.3%), after treatment with curcumin (Cheng et al., 2001).
The chemoprotective and radioprotective ability of different formula-
tions of curcumin has also been evident in the case of multiple solid
tumors (Belcaro et al., 2014). The anti-inflammatory property of this
compound played a crucial role in improving the quality of life (QoL)
of cancer patients (Panahi, Saadat, et al., 2014). For instance, in 2011,
Kim et al. reported that curcumin suppressed the expression of sali-
vary pro-inflammatory cytokines such as IL-6, IL-7, TNF-α,
granulocyte-macrophage colony-stimulating factor, and IκB kinase
beta kinase in head and neck cancer (HNC) patients (S. G. Kim
et al., 2011). Accumulating evidence from the past years have
suggested the potential anti-neoplastic activity of curcumin against
HNCs, including premalignant conditions of the oral cavity, such as
oral submucous fibrosis (OSMF), oral leukoplakia, oral mucositis, and
potentially malignant oral disorders (Delavarian et al., 2019; Kuriakose
et al., 2016; Lanjekar et al., 2020; Neetha, Panchaksharappa, Pat-
tabhiramasastry, Shivaprasad, & Venkatesh, 2020; Pinheiro
et al., 2019; Piyush, Mahajan, Singh, Ghosh, & Gupta, 2019; Rai, Kaur,
Gombra, Hasan, & Kumar, 2019; Saran et al., 2018). Topical applica-
tion of curcumin exhibited significant therapeutic effect in OSMF
patients, especially in combination with triamcinolone and hyaluroni-
dase (Lanjekar et al., 2020). Furthermore, a couple of studies are
underway to decipher the undetermined prospective of this molecule
in HNC patients (ClinicalTrials.gov Identifier: NCT01160302;
NCT04208334). Studies involving cervical cancer patients, too, have
reported beneficial effects of curcumin. In 2013, Basu et al. reported
that herbal preparation of curcumin in combination with reetha
(Indian soapberry), aloe vera, and amla (Indian gooseberry) remarkably
enhanced the clearance rate of human papillomavirus (HPV), the chief
risk factor of cervical cancer, without any side effects (Basu
et al., 2013). Several other trials have been initiated to determine the
safety, feasibility, and relapse rate of administering curcumin, both
orally and topically, and its effect in association with chemoradiation
therapy in cervical cancer patients (ClinicalTrials.gov Identifier:
NCT02554344; NCT04266275; NCT04294836; NCT02944578). In
another study comprising breast cancer patients, it was suggested that
topical application of curcumin might help to reduce radiotherapy-
associated dermatitis and pain (Ryan Wolf et al., 2020). The anticancer
potential of curcumin has also been evinced in colorectal cancer (CRC)
patients. The administration of curcumin or Curcuma extract showed a
remarkable decrease in aberrant crypt foci number, levels of PGE2,
the marker of inflammation, 3-(2-deoxy-beta-di-erythro-
pentafuranosyl)-pyr[1,2-alpha]-purin-10(3H)one (M(1)G), a known bio-
marker of lipid peroxidation and oxidative stress, and a significant
increase in the levels of the tumor suppressor gene, p53, in CRC with
standard chemotherapeutic drugs, such as folinic acid/5-fluorouracil/
oxaliplatin (FOLFOX) was also reported to be safe in metastatic CRC
patients (Carroll et al., 2011; Howells et al., 2019; Plummer
15
et al., 2001; Sharma et al., 2004). Furthermore, some clinical studies
have been investigating the anti-CRC effect of curcumin in combination
with other agents (Irving et al., 2013) (ClinicalTrials.gov Identifier:
NCT01294072). In addition, the relentless investigation has revealed
the efficacy of this molecule in pancreatic cancer patients. Studies have
advocated that curcumin alone remarkably inhibited the expression of
COX-2 and NF-κB, and phosphorylated STAT3 in pancreatic cancer
patients (Dhillon et al., 2008). Various clinical trials were piloted to
determine the safe dosage of curcumin in combination with
gemcitabine (Epelbaum et al., 2010; Kanai et al., 2011; Kanai
et al., 2013). The side effect of both these agents is also being studied
in another trial (ClinicalTrials.gov Identifier: NCT02336087). Besides
these, other clinical trials conducted in patients with cancers of the
breast, stomach, myeloid leukemia, ovary, prostate, bladder, esophagus,
testis, etc., have also demonstrated immense therapeutic benefits of
curcumin for clinical use either as monotherapy or in combination with
chemotherapy (Bayet-Robert et al., 2010; Ghalaut et al., 2012; Wolff
et al., 2012). More studies are underway to validate and understand the
mechanism of action of this multi-targeted molecule in cancer patients
(ClinicalTrials.gov Identifier: NCT03769766, NCT03980509).
3.3 | Curcumin for cardiovascular diseases
Cardiovascular diseases have the highest mortality rate among other
diseases worldwide (Roth et al., 2020). It constitutes conditions
affecting the heart or blood vessels like acute myocardial infarction,
coronary syndrome, dyslipidemia, etc. Although several drugs are
available for the treatment of cardiovascular diseases, most of them
have severe adverse effects. Herein, we discuss the impact of cur-
cumin in the patients of these diseases.
3.3.1 | Acute coronary syndrome
Acute coronary syndrome (ACS) is generally associated with reduced
blood flow to the heart, and its symptoms are clinically compatible
with acute myocardial ischemia (Kumar & Cannon, 2009). A random-
ized controlled clinical trial with 75 ACS patients was formulated to
evaluate the effects of curcumin treatment on lipidome. Three esca-
lating dosages were formulated (low dose: 45 mg/day, moderate dose:
60 mg/day, and high dose: 90 mg/day) and administered to the
patients. The outcome revealed that lower curcumin dosage levels
effectively downregulated total cholesterol and low-density lipopro-
tein (LDL) levels in patients compared with the higher dosages. The
same study also demonstrated that curcumin inhibited cholesterol and
LDL levels in a dose-dependent manner (Alwi et al., 2008).
3.3.2 | Acute myocardial infarction
Acute myocardial infarction (AMI) occurs when blood flow to the
heart is cut off, causing tissue damage. Although coronary artery
16
bypass grafting (CABG) is the conventional therapeutic approach to
tackle AMI, it is also linked to initiating myocardial infractions in
patients. Curcuminoid therapy against such patients helped to reduce
the risk of AMI significantly (Åström et al., 2020). In a study,
Wongcharoen et al. (2012) investigated the potential effect of cur-
cumin administration after the CABG surgery in a placebo-controlled
clinical study. They evaluated the frequency of acute myocardial
infraction attacks occurring during the curcumin treatment of 4 g/day
as compared with the placebo in 121 patients. The treatment cohorts
reported lower levels of CRP, N-terminal pro-B-type natriuretic pep-
tide, and malondialdehyde (MDA) (Kuriakose et al., 2016). These
effects might be due to the anti-inflammatory and antioxidant effects
of curcumin, which reduced the risk of heart attacks in patients
(Wongcharoen et al., 2012).
3.3.3 | Dyslipidemia
Dyslipidemia, as the word suggests, refers to the dysregulated lipid
profiles in the blood. High levels of LDL/cholesterol lead to clogged
arteries, which can cause a severe stroke or coronary heart disease.
This risk disorder can be prevented and reversed by an improved life-
style and proper nutrition (Cicero & Colletti, 2016). Many studies have
implicated curcumin's potential to reduce hyperlipidemia conditions. A
randomized, placebo-controlled, double-blind, cross-over trial moni-
tored the effects of curcumin supplementation (1 g/day for a month)
in 30 patients with high LDL levels. A marked decrease in serum tri-
glycerides concentrations was observed with no significant impact on
body mass index, lipid profile, and body fat. Also, curcumin administra-
tion had no significant effect on serum levels of LDL, total cholesterol,
high-density lipoprotein (HDL), and CRP (Mohammadi et al., 2013).
3.3.4 | Metabolic and cardiovascular health
Dietary supplements are extensively used to increase the immunity and
overall health of individuals worldwide. Many studies advocated the con-
sumption of curry for its anti-oxidative effects because of the presence
of curcumin and eugenol, which increases the postprandial endothelial
functions leading to improvement of overall cardiovascular health. In
another randomized controlled, cross-over trial, the consumption of curry
(Japanese food rich in spices) induced the postprandial flow-mediated
vasodilation in 14 healthy subjects as compared with the controls. Fur-
thermore, no significant change in the systemic hemodynamic or other
biological activity was observed in the patients (Nakayama et al., 2014).
A randomized longitudinal clinical trial (ClinicalTrials.gov Identifier:
NCT04458116) has started investigations to explore the correlation
between curcumin supplementation and inflammatory markers (Nrf2,
NF-κB, IL-6, TNF-α, CRP, IL-1, and IL-18), oxidative stress, and biological
functions in patients suffering from coronary artery diseases. Patients
will be given 1.5 g of 95% curcumin (ACTIVE PHARMACEUTICA LTDA)
for a month, and the expression of various genes will be monitored. In a
contrasting study, Soare et al. (2014) demonstrated that no significant
KUMAR ET AL.
correlation exists between the dietary supplements' intake and cardio-
vascular and metabolic functions in non-obese healthy individuals.
Although the treatment persisted for 24 weeks in a randomized, single-
blind controlled trial, there was no significant impact on body fat mea-
surements, arterial stiffness/endothelial function, glucose, plasma lipids,
insulin blood oxidative stress in 56 non-obese individuals. Other parame-
ters like IGF-1 and inflammatory markers were also not altered in the
treatment regimen (Soare et al., 2014).
One randomized, placebo-controlled, double-blind study measured
the correlation between the regular consumption of curcumin capsule
extracts (630 mg thrice daily) with cholesterol-related parameters. They
assessed weight, glucose, and lipid profiles in patients with metabolic
disorders both between and after the treatment in 65 patients. After
12 weeks of treatment, HDL-cholesterol levels were upregulated, and
LDL, triglycerides, and total cholesterol/HDL-cholesterol ratio were
downregulated, keeping all other biological factors like weight and glu-
cose homeostasis constant (Y. S. Yang et al., 2014). Akazawa
et al. (2012) investigated the potential of curcumin in improving vascu-
lar endothelial function. 32 postmenopausal women showed increased
vascular functions and flow-mediated dilation after oral administration
of curcumin for 8 weeks, which led to amelioration of cardiovascular
functions (Akazawa et al., 2012). Although curcumin shows immense
potential as supplementation for cardiovascular disease by reducing
inflammation and lipid dynamics, further insights by more randomized
clinical trials are paramount in establishing it as an approved drug.
3.4 | Curcumin for inflammatory diseases
Inflammatory diseases include a wide variety of disorders marked by
chronic inflammations that could be fatal. Curcumin has been proven
to be an antiinflammatory agent by many preclinical and clinical stud-
ies. It has been evaluated for many diseases such as atopic/bronchial
asthma, inflammatory bowel syndrome, oral mucositis, uveitis, peri-
odontitis, and other diseases and conditions.
3.4.1 | Biliary diseases
Oppenheimer started the first-ever human clinical trials in 1937 to
assess the effect of “curcumin” or “curcunat” extracts (mix of 0.1–
0.25 g sodium curcumin and 0.1 g calcium cholate) in human biliary
diseases. Intravenous administration of the extract (5% sodium cur-
cumin solution) in healthy individuals resulted in the rapid clearance
of the gall bladder. Interestingly, one patient showed promising result
with a complete cure throughout the treatment period
(Oppenheimer, 1937). Similarly, another double-blind, multi-centered,
prospective study used dried extracts from Schöllkraut and Curcuma
to assess the formulation potential in 76 patients with dumpy or col-
icky abdominal pain in biliary dyskinesia. Three weeks of treatment of
curcumin caused effective improvement in the pain induced by biliary
dyskinesia compared with placebo controls (Niederau &
Göpfert, 1999).
KUMAR ET AL.
3.4.2 | Bronchial asthma
Curcumin shows significant potential in the treatment of asthma. For
instance, a prospective randomized study explored the efficacy of cur-
cumin as an add-on with existing therapies in 77 bronchial asthma
patients. Curcumin capsules (500 mg twice a day for 1 month) were
found to improve airway obstruction as compared with controls, which
were seen by increased mean forced expiratory volume one second
(FEV1) values (Abidi et al., 2014). Furthermore, the treatment also led to
significant improvement in the hematological parameters, corroborating
curcumin effectiveness against this disease without any adverse side
effects. Recently, an interventional Phase II clinical trial (ClinicalTrials.
gov Identifier: NCT04353310) is recruiting to evaluate the effect of oral
curcumin supplementation (1,500 mg twice a day) in 30 patients with
moderate to severe asthma. Different parameters like asthma control
test, NO levels, total IgE, and spirometry will be evaluated in this study.
3.4.3 | Chronic anterior uveitis
Uveitis, an inflammation in the middle layer of the eyes, is a severe
complication worldwide. Chronic anterior uveitis (CAU) is one of the
few ocular disorders that does not have any uniformity, standardiza-
tion and poses limited clinical options (McCluskey, Towler, &
Lightman, 2000). Although curcumin is effective against a wide range
of inflammatory disorders, very few clinical trials have initiated inves-
tigations to divulge into these diseases. One such study used oral
administration of curcumin to explore its efficacy in CAU patients.
Oral administration of curcumin with 375 mg thrice a day for
12 weeks with anti-tubercular therapy improved the response rate to
86% in 32 patients. Although curcumin improved the overall health of
the patients, follow-up after 3 years had a 55% recurrence rate (Lal
et al., 1999). Similarly, another group explored the effectiveness of
the Meriva® (600 mg of phospholipidic curcumin) on CAU of different
etiologies in 106 patients with 12 months follow-up period. They
reported that the administration of curcumin is safe and well-tolerated
and reduced eye discomfort, signs and symptoms in more than 80%
of patients (Allegri et al., 2010). Also, the study suggested the promis-
ing benefits of curcumin in other eye-related inflammatory disorders
like glaucoma, dry eye, maculopathy, and diabetic retinopathy.
Although curcumin showed a promising effect in the palliative care of
CAU patients, more clinical trials are needed for the establishment of
the efficacy of curcumin for these diseases.
3.4.4 | Chronic cutaneous complications
Chronic cutaneous complications generally arise during the continu-
ous subcutaneous insulin infusion or sulfur mustard (SM) exposure
(Panahi, Sahebkar, Parvin, et al., 2012). Curcumin exhibits strong anti-
inflammatory potential against this disease. Panahai, Sahebkar, Parvin,
et al. (2012) explored the anti-inflammatory potential of curcumin
with the serum biomarkers, IL-8, hs-CRP, calcitonin gene-related
17
peptide (CGRP), and QoL in 96 patients suffering from a chronic cuta-
neous disease named pruritus, and the treatment was found to be
effective. The same group also studied the effect of curcumin
(C3 complex® capsules each of 500 mg curcuminoids with 5 mg of
bioperine for 4 weeks) in a randomized controlled trial of this disease.
This finding indicated curcumin to be efficacious in reducing the SM-
induced cutaneous inflammations and inflammatory markers in
patients, and their association can be an indicator of improved QoL in
pruritus patients. However, there were no significant changes in the
IL-6 levels (Panahi, Sahebkar, Parvin, & Saadat, 2012).
3.4.5 | Chronic periodontitis
Chronic periodontitis is a common oral cavity disorder that results in
periodontal tissue inflammation because of increased dental plaque
(Cardoso et al., 2018). Different approaches of curcumin (supplement
or gel-based form) have been used as potential therapeutics to circum-
vent and prevent chronic periodontitis. A nonsurgical, retro-prospective
approach compared the effect of curcumin collagen gel (1% wt/vol
aqueous solution of collagen sponge containing 50 mg/cm2 of cur-
cumin extracts) with the conventional chlorohexidine (CHX) as adjuncts
in scaling and root planning for 60 chronic periodontitis patients. The
efficacy of the treatment was explored by monitoring the pocket depth
and clinical attachment levels after 6 months in patients. This study
showed a substantial decrease in gingival plaque index (PI), probing
pocket depth (PPD) scores with ameliorated microbial parameters
(microbial colony count, N-benzoyl-DL-arginine-2-napthylamide test),
indicating curcumin's efficiency in curbing the symptoms of chronic
periodontitis patients (Gottumukkala et al., 2014). Similar studies have
also reported the use of 1% of curcumin as a supplement to irrigate the
scale and root plan in chronic periodontitis patients (Gottumukkala
et al., 2013; Suhag, Dixit, & Prakash, 2007). Further, administration of
curcumin ameliorated inflammatory symptoms in different cases of
chronic periodontitis patients. Subsequent study has reported that the
use of 2% whole turmeric gel exhibited higher pharmacological activity
in the palliative care and management of periodontal pockets in
30 patients having chronic localized or generalized periodontitis. Differ-
ent parameters like PPD, PI, sulcus bleeding index, gingival index (GI),
and relative attachment loss (RAL) were reduced in the curcumin-
treated groups when compared with the respective controls (Behal
et al., 2011). A double-blinded, randomized Phase III clinical trial
(ClinicalTrials.gov Identifier: NCT03790605) is ongoing to explore the
efficacy of the treatment of 1% curcumin chips locally in a nonsurgical
isolated periodontal pocket of 40 patients. The study groups will be
compared based on the effect on cytokine parameters (IL-1β) and dif-
ferent experimental index (PI, GI, RAL, PPD).
3.4.6 | Gingivitis
Gingivitis is a common periodontal disorder that afflicts more than
80% of the population worldwide (Pulikkotil & Nath, 2015). It arises
18
primarily due to the accumulation of plaque or bacteria that leads to
inflammation of gums. Curcumin is a well-known anti-inflammatory
molecule, and hence its mouth wash formulations were equally effec-
tive as conventional CHX in patients and can be used as a supplement
in gingivitis and periodontal therapy (Muglikar et al., 2013). Another
study investigated the efficacy of the treatment of curcumin in combi-
nation with CHX and chlorhexidine-metronidazole in 60 subjects. In
this study, curcumin gel (10 mg extracts) treatment was found to be
safe, well-tolerated, efficacious, and it downregulated the chemokine
(C-C motif) ligand 28 (CCL28) and IL-1β levels better than the conven-
tional combinatorial formulations (Pulikkotil & Nath, 2015). Similarly,
another randomized study involving 100 patients demonstrated that
the whole turmeric formulation exhibited a similar response as cur-
cumin extracts and chlorhexidine gluconate in the prevention and
treatment of plaque and gingivitis. Although there was a reduction in
PI and mean GI in curcumin-treated cohorts, CHX gluconate exhibited
better antiplaque activity (Waghmare et al., 2011).
3.4.7 | Oral lichen planus
Oral lichen planus (OLP) is a chronic condition that constitutes the
inflammation in mucous membranes of the oral cavity. Curcumin-
based therapeutics have been studied in OLP, deeming it safe and
well-tolerated in patients. Chainani-Wu and his group conducted a
randomized placebo-controlled clinical trial with 100 OLP patients to
explore the efficacy of curcuminoids. In this study, curcumin was
administered at 2,000 mg/day for 7 weeks to the first group of
patients. Although this study was not complete, the authors suggested
that the curcumin treatment with a higher dosage should be consid-
ered for further studies (Chainani-Wu et al., 2007). In another clinical
setting by the same group, 6,000 mg/day of curcuminoid in
20 patients were found to be safe in the escalating doses and also hel-
ped in improving the symptoms of OLP (Chainani-Wu, Madden,
et al., 2012). Another clinical trial used a similar dose of 6,000 mg/day
in 53 OLP patients. These findings demonstrated that curcumin
reduces the signs and symptoms in more than 60% of patients validat-
ing the potential of curcumin to prune this disorder (Chainani-Wu,
Collins, & Silverman Jr., 2012). Further, a phase I clinical trial
(ClinicalTrials.gov Identifier: NCT03877679) is exploring the efficacy
of curcumin paste in abating the pain and clinical levels of IL-33 in the
saliva of 40 OLP patients. Furthermore, this study also aims to com-
pare the treatment outcome of novel curcumin formulations with con-
ventional therapeutics (corticosteroids).
3.4.8 | Chronic pulmonary complications
Chronic pulmonary complication (CPC) is a group of lung disorders
that are generally related to SM intoxication (Ghasemi et al., 2013).
Panahi, Ghanei, et al. (2015) investigated the potential of curcumin in
patients with CPC instigated by SM. A double-blind, randomized study
KUMAR ET AL.
recruited 89 subjects and divided the groups into curcumin (500 mg
thrice a day) treatment and placebo control for 4 weeks. It was shown
that curcumin exhibited antiinflammatory activity by modulating vari-
ous mediators IL-8, IL-6, TNF-α, hs-CRP, substance P, CGRP, TGF-β,
monocyte chemotactic protein-1, etc. Further, the treatment of cur-
cumin reduced the spirometric parameters and FEV1/forced vital
capacity ratio in treated groups (Panahi, Ghanei, et al., 2015). This trial
also concluded that the curcuminoid was safe and well-tolerated in
patients throughout the treatment period, and short-term adjuvant
therapy is successful in patients suffering from systemic SM-induced
pulmonary complications (Panahi, Ghanei, et al., 2015).
3.4.9 | Chronic kidney disease
Chronic kidney disease (CKD) is a disorder marked by loss of renal
functions, over time with increased inflammation (Drawz & Rahman,
2015). To evaluate the safety and efficacy of curcumin in CKD,
Moreillon et al. (2013) used a herbal supplement (C. longa and
Boswellia serrata) or placebo to treat 16 non-dialysis CKD patients.
Plasma levels were monitored for the change in TNF-α, IL-6, serum
CRP, and glutathione peroxidase molecules at baseline and after
8 weeks. Curcumin was observed to be well-tolerated and safe in
patients with decreased inflammatory IL-6 levels (Moreillon
et al., 2013). A randomized, double-blind pilot study evaluated the
effect of curcumin juice on the pro-inflammatory markers in 31 CKD
patients. Orange juice supplemented with 12 g curcumin was adminis-
tered for 3 months, which resulted in reduced levels of inflammatory
markers, NF-κB, and hs-CRP levels (Alvarenga et al., 2020). A cross-
over randomized clinical trial (ClinicalTrials.gov Identifier:
NCT04413266) is recruiting to assess the effect of curcumin supple-
mentation (500 mg of curcumin and piperine thrice a day, for
12 weeks) on inflammation, intestinal microbiota, uremic toxins, and
inflammasome in 30 patients with CKD under peritoneal dialysis. This
study focuses on evaluating the significant inflammatory markers
(nuclear receptor factor 2 (Nrf2), glutathione peroxidase, IL-6, TNF-α,
IL-18, and inflammasome) in order to compare the efficacy of
curcumin.
3.4.10 | Gastritis
Gastritis is the inflammation in the lining of the stomach caused
mainly by Helicobacter pylori (Sipponen & Maaroos, 2015). Seeing
curcumin's anti-inflammatory properties, a pilot study was conducted
by Koosirirat et al. (2010) to evaluate the therapeutic possibility of
curcumin on H. pylori-infected gastritis patients. It was shown that
curcumin had a minimal effect in decreasing the H. pylori-induced
cytokines like IL-8, TNF-α, and COX-2. Still, other studies have
reported the improvement in patients' signs and symptoms suffering
from gastritis after the administration of curcumin (Koosirirat
et al., 2010).
KUMAR ET AL.
3.4.11 | Inflammatory bowel disease
Inflammatory bowel disease (IBD) is a relapsing disorder characterized
by inflammation of the gut and includes two disorders, namely,
Crohn's disease and ulcerative colitis (UC) (Aguas, Del Hoyo, Faubel, &
Nos, 2016). Although mortality among IBD disorders is very few, it
still severely hampers the patient's QoL due to early-stage onset and
challenges in chronicity (Simian et al., 2016). Also, if left unchecked, it
leads to the formation of adenocarcinoma and is reported to be asso-
ciated with the initiation of blood-related cancers (Wheat
et al., 2016). As curcumin is well-proven to be an anti-inflammatory
agent, a forced dosage titration study was investigated to procure a
plausible efficacious dosage for 11 pediatric IBD patients. Firstly, the
curcumin was administered at 1,000 mg a day for 3 weeks, and then it
was increased to 2,000 mg for 3 weeks, and at the end, the dosage
was increased to 3,000 mg for the last 3 weeks. Although the dosage
was well-tolerated and showed overall improvement in symptoms of
inflammation with a reduction in pediatric UC activity index, induction
of gassiness was reported in some patients (Suskind et al., 2013).
Recently, in a combinatorial, randomized clinical trial (ClinicalTrials.gov
Identifier: NCT03500653), curcumin is being used as an add-on to
improve the efficiency of vedolizumab therapy in IBD patients. In this
study, 4 g of curcumin with 300 mg per infusion of vedolizumab will
be administered daily for a year in 100 test subjects, and Harvey–
Bradshaw index will be calculated for assessing the combinatorial
approach.
3.4.12 | Crohn's disease
Crohn's disease is a type of IBD that has recently become prevalent
worldwide and is majorly caused by immune dysregulation and gene
mutations (Lauro, Burch, & Grimes, 2016; Manuc, Manuc, &
Diculescu, 2016). An investigational open-label pilot study was carried
out to determine the potential of curcumin as an adjunct with the
other conventional treatments (corticosteroid, 5-aminosalicylic acid
compounds, and 10 mg prednisone) to abate inflammation. This was
achieved by decreasing the concentrations of other concomitants to
curcumin in a forced dosage titration approach. Curcumin was admin-
istered at the dose of 550 mg twice a day for 1 month and 550 mg
thrice a day for another month. Lower sedimentation rate and Crohn's
disease activity index were observed in 4 out of 5 patients corroborat-
ing the potential of curcumin in combating this disease (Holt
et al., 2005). A randomized, single-blind clinical trial (ClinicalTrials.gov
Identifier: NCT04431700) is active to assess the impact of
antiinflammatory dietary food diet in management of Crohn's disease
in 116 test subjects.
3.4.13 | Ulcerative colitis
Ulcerative colitis (UC) is a commonly occurring IBD in the innermost
lining of the large intestine (colon) or rectum (Ordás et al., 2012).
19
Accumulating evidence has implicated the usefulness of curcumin-
based therapeutics in various in vitro and in vivo models of UC. In one
randomized, single-centered, double-blind pilot trial, the standard for-
mulation of NCB-02 (curcumin extracts) was used as an enema in
45 UC patients. NCB-02 is a standard well-known form of curcumin,
containing 72% of curcumin, 18.08% of demethoxy curcumin and
9.42% of bis-demethoxy curcumin in the formulation. The same study
showed a reduction of inflammatory markers with amelioration in
endoscopic activity and disease recurrence as a result of curcuminoid
administration (Singla et al., 2014). In other multi-centered, random-
ized pilot studies, the effects of curcumin therapy were explored in
UC patients as an adjuvant undergoing mesalamine/sulfasalazine ther-
apy. Curcumin exerted its effects by increasing the clinical activity
index and endoscopic indices, thereby preventing the morbidities
associate with UC (Hanai et al., 2006; Lang et al., 2015). Recently, a
randomized, double-blind Phase III clinical trial (ClinicalTrials.gov Iden-
tifier: NCT02277223) is ongoing to inspect the curcuminoid's efficacy
as complementary mediation in the induction and management of
60 UC patients. A maintenance regimen approach will be followed
where curcumin treatment will be given based on the individual's
weight. Thus, the use of curcumin as an adjunct or drug can be an
alternative therapeutic approach circumventing and regulating relapse
in UC patients.
3.4.14 | Osteoarthritis
Osteoarthritis (OA) is the most common form of arthritis afflicting
millions of people worldwide. Treatment for OA is limited, and a lot
of challenges exist for the clinical management of this disease. In
vitro and in vivo results clearly show promising and beneficial effects
in abating OA (Henrotin et al., 2014). A controlled randomized,
double-blind clinical trial was conducted to determine the efficacy
and safety of curcumin C3 complex® treatment in 40 OA patients.
Curcumin was found to be safe and well-tolerated in patients suf-
fering from knee OA. Administration of curcuminoid (C3 complex®
at 1,500 mg/day) brought about decreased physical function (visual
analog scale [VAS]) and pain scores (Lequesne's pain functional
index [LPFI] scores) but was minimally effective in stiffness core OA
index (Panahi, Rahimnia, et al., 2014). Another exploratory non-
controlled study evaluated the treatment of curcumin in 22 OA
patients by monitoring the specific biomarkers (CRP,
myeloperoxidase, collagen type II alpha 1 [Coll-2-1], nitrated form
of Coll2-1 [Coll-2-1NO2], fibulin 3 [Fib3]-1, Fib3-2, and C-terminal
cross-linked telopeptide of type II collagen). Low expression of
Col2-1 and CRP was associated with efficacious therapeutic out-
comes of curcumin. There were no significant changes in the serum
levels of other biomarkers in this study (Henrotin et al., 2014). Fur-
ther, the treatment of 1,000 mg/day of curcumin was also found to
be efficient when used in combination with diclofenac (75 mg/day
for 3 months) in the treatment of OA patients. Furthermore, it was
shown to abate pain and improve the health functions in OA
patients (Pinsornsak & Niempoog, 2012).
20
In a pilot study conducted in 367 patients, treatment with the
extracts of Curcuma domestica at 1,500 mg/day for 4 weeks resulted
in amelioration of the OA index, and its therapeutic efficacy was com-
parable to ibuprofen (Kuptniratsaikul et al., 2014). Further, different
formulations have been devised and marketed for improving the bio-
availability of curcumin for OA patients. In one randomized, placebo-
®
controlled, double-blind, prospective study, Theracurmin , a bioavail-
able form containing 180 mg of curcumin (made by Thera values Cor-
poration, Kioicho, Tokyo, Japan), was used to explore its potency
against 50 OA patients above 40 years. It was found to be successful
against the patients by reducing the pain index (VAS) and inducing no
adverse toxic effects after the follow-up of 8 weeks (Nakagawa
et al., 2014). In addition, Meriva®, a combination of curcumin and soy
phosphatidylcholine, was reported to be highly potent in the manage-
ment of OA. Also, it has greater bioavailability and helps to increase
the biochemical activity and overall clinical functions in OA patients
(Belcaro et al., 2010b; Belcaro et al., 2014).
3.4.15 | Rheumatoid arthritis
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease
with limited treatment strategies (Smolen et al., 2016). Chandran and
Goel (2012) conducted a randomized pilot study to explore the pros-
pect of curcumin in the treatment of RA in 45 patients in combination
with diclofenac sodium. Different groups received curcumin (500 mg),
diclofenac sodium (50 mg), and a combination of both. Significant
improvement in the American College of Rheumatology scores and
disease activity scores were reported after the treatment in the com-
binatorial group. Also, they demonstrated the administration of cur-
cumin was safe and well-tolerated in patients (Chandran &
Goel, 2012). Besides, curcumin (2 g/day) was shown to decrease the
swelling and stiffness in joints with a combination of mesalamine/
sulfasalazine in 45 RA patients, indicating an effective treatment for
this disease (Hanai et al., 2006). Thus, these findings corroborate
curcumin's pivotal role in circumventing inflammatory-based
disorders.
3.4.16 | Peptic ulcer
Peptic ulcers are common bowel disorders formed either by infections
from H. pylori or deregulation of stomach acids (Farzaei, Abdollahi, &
Rahimi, 2015). Curcumin being an anti-inflammatory agent could play
a vital role in palliative care and management of this disorder. For
instance, a Phase II randomized clinical trial addressed the healing
properties of turmeric on peptic ulcers. Oral administration of cap-
sules, each 300 mg five times a day, was given to 25 patients having
ulcers at the duodenal bulb and gastric (angulus). This study reported
that some patients showed complete cure by 8 weeks of the treat-
ment, and few patients did not have ulcers for more than 12 weeks
(Prucksunand et al., 2001). This itself shows the potential of this com-
pound against the prevention and treatment of peptic ulcers.
KUMAR ET AL.
3.5 | Curcumin for metabolic disease
Metabolic disorders are a cluster of conditions that occur due to
abnormal chemical changes or deficient enzymatic machinery involved
in metabolism. Preclinical evaluation of curcumin for metabolic dis-
eases like diabetes and obesity has already been explored and showed
favorable results in the management of these disorders.
3.5.1 | Diabetes
Diabetes is characterized by abnormal sugar levels in the blood
(Kerner & Brückel, 2014). Although targeted treatments are still being
developed, a wide spectrum targeted approach like curcumin could
help in combating and preventing diabetes. The first study was con-
ducted by Srinivas in 1972 to check the efficacy of curcumin in reduc-
ing the blood sugar levels in patients. Administration of curcumin
reduced the blood sugar levels from 1,400 to 700 mg/L in a patient
who had been diabetic for 16 years (Srinivasan, 1972). In another ran-
domized, placebo-controlled, parallel-group clinical trial, the efficacy
of NCB-02 and atorvastatin was explored in 72 type II diabetic
patients. Patients received either NCB-02 (300 mg/day) or atorva-
statin (10 mg/day) for 8 weeks, and their endothelial functions and
biomarkers were evaluated in test subjects and placebo controls.
Curcumin-based therapeutics showed a remarkable effect in decreas-
ing pro-inflammatory cytokines (IL-6 and TNF-α) and other oxidative
stress markers (MDA and endothelin-1) in these patients (Usharani
et al., 2008). In another randomized, placebo-controlled, double-blind
study involving 260 patients with pre-criteria of diabetes, the potency
of curcumin (750 mg/day) was noted in abating the development and
progression of type II diabetes mellitus. Curcumin treatment increased
the homeostatic model assessment (HOMA)-β, beta-cell attributes,
and adiponectin with downregulation of HOMA for insulin resistance
and C-peptide levels as compared with respective placebo groups
(Chuengsamarn et al., 2012). Further, the study also revealed that cur-
cumin could adjust the metabolic setting and decrease atherogenic
risks in high prospect populations (Chuengsamarn et al., 2014). Na
et al. (2014) also showed that the treatment of type II diabetic
patients with curcumin reduced blood sugar levels and different
serum markers like adipocyte fatty acid binding protein, CRP, TNF-α,
and IL-6 levels (Na et al., 2014). Besides, Meriva® was found to have a
pharmacological effect against retinopathy and diabetic micro-
angiopathy (Appendino et al., 2011; Steigerwalt et al., 2012).
3.5.2 | Obesity
Obesity is a recent public health challenge where excess fat accumula-
tion in the body leads to other significant disorders of the body
(Ganjali et al., 2014). In a cross-over, double-blind study, curcumin
(1 g/day) treatment has shown exciting results in repressing anxiety
(Beck Anxiety Inventory scores) and depression (Beck Depression
Inventory scales) associated with obesity in 30 patients (Esmaily
KUMAR ET AL.
et al., 2015). Furthermore, by regulating IL-β, IL-4, and TGF-β expres-
sion levels, curcumin showed immunomodulatory effects and reduced
oxidative stress in obese individuals (Ganjali et al., 2014; Sahebkar,
Cicero, Simental-Mendía, Aggarwal, & Gupta, 2016). In addition, a ran-
domized clinical trial (ClinicalTrials.gov Identifier: NCT03670875) of
curcumin (600 mg) supplementation with other dietary adjuncts like
omega-3-fatty is being explored as a non-pharmacological alternative
for pediatric obesity in 300 subjects.
3.6 | Curcumin for neurological disease
Neurological diseases are disorders of the central and peripheral ner-
vous systems. Very few treatment modalities exist for neurological
disorders because the mechanistic cues of these diseases have not
been fully understood. Curcumin has also been explored for certain
neurological diseases like Alzheimer's, Schizophrenia, and depression
in clinical trials.
3.6.1 | Alzheimer's disease
Alzheimer's disease is a progressive neurodegenerative disease
resulting in loss of brain functions like memory and cognitive abilities
(Lane et al., 2018). A random, double-blind placebo-controlled clinical
trial was investigated to examine the prospect of curcumin in
34 patients sufferring from Alzheimer's disease. Two different dos-
ages (1 g and 4 g) and a placebo group were used to evaluate the
study parameters. Intake of curcumin resulted in an increase in the
level of vitamin E with no adverse side effects portraying the anti-
oxidative attributes of curcumin (Baum et al., 2008; Gupta, Patchva, &
Aggarwal, 2013).
3.6.2 | Depression
Depression is a neurological disorder with varied pathways and tar-
gets involved in disease progression. Curcumin is observed to target
multiple pathways and affect disease biomarkers of depression and
improve the psychological state of the patients (Lopresti et al., 2014;
Lopresti et al., 2015). Sanmukhani et al. (2014) investigated the effect
of curcumin treatment with fluoxetine in a randomized controlled clin-
ical trial involving 60 patients suffering from a major depressive disor-
der. The study was divided into three groups of curcumin alone
(1,000 mg), fluoxetine (20 mg), and their combination. The combinato-
rial approach was found to ameliorate the psychological state without
a trace of suicidal ideation and other psychological disorders
(Sanmukhani et al., 2014). Similarly, another randomized, placebo-
controlled clinical trial concluded curcumin (1 g/day for 8 weeks) to
be effective in abating the mood-related symptoms of 56 patients suf-
fering from depression (Lopresti et al., 2014). Furthermore, the same
group reported that the treatment of curcumin (500 mg twice a day)
for 8 weeks led to the modulation of several markers like cortisol,
21
aldosterone, substance P, thromboxane B2, leptin, endothelin-1, indi-
cating its anti-depressant properties (Lopresti et al., 2015).
3.7 | Curcumin for skin diseases
Curcumin is highly promising and potent against various skin condi-
tions like psoriasis, vitiligo, and radiation-induced dermatitis.
3.7.1 | Psoriasis
Psoriasis is an autoimmune disease marked by abnormal red rashes
with silvery-white patches all over the skin (Kamiya et al., 2019). Cur-
cumin (diferuloylmethane) has been demonstrated to alter phosphory-
lase kinase levels in psoriasis patients through the inhibition of
keratinocyte transferrin receptor, and epidermal CD8+ T cells, and
hence reducing the severity of parakeratosis (Heng et al., 2000). A
random, placebo-controlled, double-blind study explored the efficacy
of Meriva®, with a lecithin-based delivery system in treating 63 psoria-
sis patients. The treatment of Meriva® (2 g/day) for 12 weeks showed
a decrease in disease conditions, and, when combined with topical
steroids, it increased their therapeutic efficiency. It was also found to
be potent against psoriasis vulgaris by reducing the serum levels of IL-
22 (Antiga et al., 2015). A Phase II, Simon two-stage open-label trial
was conducted to investigate the response of curcumin C3 complex®
in plaque psoriasis patients. The participants received 4.5 g of C3
complex daily, which was found to improve the symptoms with no
notable adverse effects (Kurd et al., 2008).
3.7.2 | Dermatitis
Dermatitis is a generic term for skin irritations. Studies have shown the
potential of curcumin in reducing the symptoms of dermatitis induced
by other therapies. A randomized, double-blind, placebo-controlled clin-
ical trial assessed curcumin's efficiency in reducing the severity of dis-
ease conditions in 30 breast cancer patients suffering from radiation-
induced dermatitis. 6 g/day of curcumin was sufficient to decrease der-
matitis symptoms in radiotherapy sessions (Ryan et al., 2013). Another
Phase III clinical trial (ClinicalTrials.gov Identifier: NCT01246973) with
the same group is ongoing in 686 breast cancer participants to deter-
mine curcumin's efficiency (C3 complex®, 2 g/day) in decreasing the
severity of skin reactions during radiation therapy.
3.7.3 | Vitiligo
Vitiligo is a skin condition that is marked by the loss of pigmentation
in skin cells. Asawanonda and Klahan (2010) reported that the topical
combinatorial treatment of narrow-band UVB (308-nm excimer laser)
plus tetrahydrocurcuminoid cream was safe and effective for vitiligo
patients (Asawanonda & Klahan, 2010).
22
3.8 | Curcumin for infectious diseases
Curcumin shows effective therapeutic outcomes in the management
and treatment of various infectious diseases in humans.
3.8.1 | Acquired immunodeficiency syndrome
Acquired immunodeficiency syndrome (AIDS) is caused by the human
immunodeficiency virus (HIV), which hijacks the immune system and
weakens the normal physiological process of the body (Sauter &
Kirchhoff, 2016). Studies have also evaluated the antiviral potential of
curcumin against HIV AIDS. In line with this, a randomized study was
initiated by New England to explore curcumin's efficacy as an antiviral
agent in 40 AIDS patients. Two different cohorts with a high dose
(2.5 g/day) and a low dose group were formulated and were adminis-
tered for 8 weeks. This study showed that curcumin treatment
increased CD4 cells in the high dose cohort as compared with the low
dose cohort (James, 1996).
3.8.2 | Hepatic disorders
Curcumin is highly efficacious in the treatment of different hepatic
diseases like alcoholic liver disease, nonalcoholic fatty liver disease,
hepatitis B, hepatitis C, liver cancer, biliary cirrhosis, drug-induced
hepatotoxicity, etc. Curcumin targeting NF-κB, one of the key players
in inflammation, accounts for its remarkable potential on various liver
diseases (Nabavi, Daglia, Moghaddam, Habtemariam, & Nabavi, 2014;
Nanji et al., 2003; Rivera-Espinoza & Muriel, 2009). Several preclinical
studies on animal models reported the reduction of liver damage with
the treatment of curcumin (Bruck et al., 2007). A known concoction of
C. longa (enriched with 25% curcumin, 1 g/day) and Tinospora cor-
difolia (1 g/day extracts) successfully suppressed the hepatotoxicity
caused by anti-tuberculosis drugs, with no significant toxic effects in
528 patients (Adhvaryu et al., 2008). A single-center, Phase II, ran-
domized, double-blinded, clinical trial (ClinicalTrials.gov Identifier:
NCT04109742) is recruiting to investigate the potential of curcumin
in pediatric non-alcoholic fatty liver disease. Two escalating dosages
(500 mg and 1,000 mg/day) of Meriva® will be administered orally to
30 patients, and serum ALT level will be monitored to establish the
therapeutic outcome. Similarly, another randomized trial
(ClinicalTrials.gov Identifier: NCT03864783) is also recruiting to
assess the efficacy of Meriva® (500 mg tablet, twice a day) on liver fat
content in obese patients.
3.8.3 | Other diseases
Curcumin's innate propensity to target multiple pathways can be ben-
eficial for many other diseases like arsenic carcinogenicity and dys-
phasia. Curcumin, with its anti-oxidative attributes, could help in
alleviating the toxic effects linked with arsenic. In one field study,
KUMAR ET AL.
curcumin intervention in patients with groundwater arsenic contami-
nation resulted in decreased DNA damage, ROS generation, lipid per-
oxidation, and increased antioxidant activity (Biswas et al., 2010). It
has been proven to reduce oxidative stress generated from exercises
and modulate the level of neurotransmitter in premenstrual syndrome
in women (Khayat et al., 2015; Takahashi et al., 2014). Further, the
oral intake of curcumin-based therapeutics (500 mg/day for
12 months) decreased oxidative stress and damage in 21 β-thalasse-
mia/Hb E patients. However, withdrawal from the curcumin-based
therapeutics after 3 months reversed these effects (Kalpravidh
et al., 2010). Besides, curcumin was also reported to increase the QoL
of a 15-year-old Déjérine–Sottas patient (Burns et al., 2009). In addi-
tion, administration of curcuminoids showed positive therapeutic out-
comes in patients who had undergone laparoscopic cholecystectomy
(Agarwal et al., 2011). In another randomized clinical trial, Panahi,
Sahebkar, Amiri, et al. (2012) demonstrated the efficiency of curcumin
to suppress inflammatory mediators and ameliorate the QoL in pruri-
tus patients (Panahi, Sahebkar, Amiri, et al., 2012). Furthermore, oral
intake of curcumin reduced signs of lupus nephritis and paraprotein
levels in patients with monoclonal gammopathy of undetermined sig-
nificance (MGUS) (Golombick et al., 2009). The same group also
showed that the treatment of curcumin inhibited disease progression
in MGUS and multiple myeloma patients (Golombick et al., 2012). Cur-
rently, the world is crippled by SARS-CoV-2, officially named COVID
19. In one recent randomized study, oral administration of curcumin
C3 complex® (525 mg of curcumin and 2.5 mg of bioperine) in
30 COVID 19 infected patients experiencing mild to moderate symp-
toms resulted in early recovery of symptoms like fever, cough, sore
throat, and breathlessness, with better clinical outcomes as compared
with the controls (Pawar et al., 2021).
4 | CONC LU SION AND F UTU RE
PROSPECTS
Finding a potential and nontoxic multi-targeted drug that is effective
against a wide range of diseases is still like converting vision to reality
for researchers worldwide. Most of the compounds that show signifi-
cant outcomes in preclinical studies somehow fail to exert similar
effects in clinical settings. However, curcumin is one such polyphenol
that has shown a promising impact in preclinical and clinical studies.
Numerous clinical trials have demonstrated that curcumin is effective
against different types of cancers, cardiovascular diseases, inflamma-
tory diseases, metabolic diseases, skin diseases, neurological diseases,
infectious diseases, and several others. Curcumin effectively relieves
signs and symptoms of diseases, reduces the level of biomarkers,
enhances the QoL, slows down the progression, and prevents relapse
of diseases in patients. It also showed great potency when used as
adjuvant therapy. Furthermore, treatment with curcumin was found
to sensitize the cancer cells to chemo- and radiation therapy. Most
importantly, curcumin treatment was found to be safe, highly bioavail-
able, and well-tolerated, and it did not result in any adverse side
effects. Further, when administered to healthy volunteers, the drug
KUMAR ET AL.
was found to impart multiple health benefits and improve blood pres-
sure and heart rate. Although this study focuses on the favorable
properties of curcumin, it is relevant to point out few incidences that
reported its minimal side effects. This has led to widespread criticism
of curcumin's ability and its safety regarding its usage as a generic
drug, the most pertaining one being its poor bioavailability. Curcumin
is extensively metabolized in the liver and intestines, and hence the
required pharmacological concentrations in the plasma and tissues are
not achieved even after administration of higher dosages of curcumin

n, Caldero
(Burgos-Moro
n-Montaño, Salvador, Robles, & Lo

pez-
Lázaro, 2010). Few studies have demonstrated that the plasma levels
in patients taking higher concentrations of curcumin are only in the

pez-Lázaro, 2008; Vareed et al., 2008). There are
nanomolar range (Lo
also reports of the patients receiving 500–12,000 mg in a dose–
response study, experiencing symptoms like diarrhea, headache,
rashes, and yellow stool (Hewlings & Kalman, 2017). Also, one study
in 1976 by Goodpasture and Arrighi showed that curcumin could
cause dose and time-dependent aberrations in chromosomal DNA at
10 μg/ml (Goodpasture & Arrighi, 1976). Still, these minimal adverse
effects cannot overshadow the immense pharmacological and medici-
nal value of curcumin in treating various chronic diseases. The signifi-
cant limitations of some of the clinical trials listed here are that firstly,
low dosage of curcumin has been investigated in these studies to con-
clude the efficacy of the nutraceutical, and secondly, treatment in
some of the studies has used lower bioavailable forms of curcumin.
Most importantly, for curcumin to be developed as a therapeutic
drug, clinical trials focusing on dosage levels and their effects on
short-term and long-term toxicity need to be explored. Recent inno-
vations in the research have brought various novel bioavailable formu-
lations of curcumin, and these new biocompatible compounds need to
be clinically tested in random, placebo-controlled, multi-centered trials
in order to acknowledge curcumin's immense potential in combating
different chronic diseases. Thus, curcumin undoubtedly has the poten-
tial to be considered as the leading edge to discover treatment strate-
gies for the prevention and treatment of different chronic diseases.
ACKNOWLEDGEMEN TS
This work is supported by RBMH/PNH/SB/12/2015-1428 grant
awarded to Dr Ajaikumar B. Kunnumakkara, by Indian Council of
Medical Research (ICMR), New Delhi, Government of India.
CONF LICT OF IN TE RE ST
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work in this paper.
DATA AVAI LAB ILITY S TATEMENT
Data sharing is not applicable to this article as no new data were gen-
erated, and the article describes entirely theoretical research.
ORCID
Ajaikumar B. Kunnumakkara https://orcid.org/0000-0001-9121-
6816
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How to cite this article: Kumar, A., Harsha, C., Parama, D.,
Girisa, S., Daimary, U. D., Mao, X., & Kunnumakkara, A. B.
(2021). Current clinical developments in curcumin-based
therapeutics for cancer and chronic diseases. Phytotherapy
Research, 1–34. https://doi.org/10.1002/ptr.7264