Role of Turmeric and Curcumin in Prevention and Treatment of Chronic Diseases: Lessons Learned from Clinical Trials

Abstract

Turmeric (Curcuma longa) has been used for thousands of years for the prevention and treatment of various chronic diseases. Curcumin is just one of >200 ingredients in turmeric. Almost 7000 scientific papers on turmeric and almost 20,000 on curcumin have been published in PubMed. Scientific reports based on cell culture or animal studies are often not reproducible in humans. Therefore, human clinical trials are the best indicators for the prevention and treatment of a disease using a given agent/drug. Herein, we conducted an extensive literature survey on PubMed and Scopus following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The keywords “turmeric and clinical trials” and “curcumin and clinical trials” were considered for data mining. A total of 148 references were found to be relevant for the key term “turmeric and clinical trials”, of which 70 were common in both PubMed and Scopus, 44 were unique to PubMed, and 34 were unique to Scopus. Similarly, for the search term “curcumin and clinical trials”, 440 references were found to be relevant, of which 70 were unique to PubMed, 110 were unique to Scopus, and 260 were common to both databases. These studies show that the golden spice has enormous health and medicinal benefits for humans. This Review will extract and summarize the lessons learned about turmeric and curcumin in the prevention and treatment of chronic diseases based on clinical trials.

Chronic diseases are the leading causes of mortality and disability globally, and there has been a pronounced rise in cases in recent years.¹⁻³ A vast majority of chronic disorders co-occur, making it difficult to find plausible therapeutic interventions. Despite remarkable advances in treatment regimens, the global incidence of chronic diseases has increased at a phenomenal rate. Deadly diseases, such as cancer as well as cardiovascular, hepatocellular, and neurological disorders are caused by aberrations in numerous biological and cellular processes. Therefore, relying on a specific pathway among several implicated molecular signatures will unlikely be beneficial in preventing and treating various chronic illnesses.⁴⁻⁶ Modern medications come with a steep price tag and a slew of adverse side effects. Therefore, increasing attention has been paid to natural products to find novel drugs for the prevention and treatment of various diseases.⁶⁻²³ Natural compounds exhibit diverse biological activities and drug-like properties, because of which they have become a vital resource for developing new lead compounds to discover drugs for treating human diseases, particularly chronic diseases.^13,24−27 They have a remarkable role in human health and disease prevention and act as a powerful means of promoting optimal health, longevity, and quality of life (QoL).^1,28−30

Curcumin, also known as diferuloylmethane or (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, is a phenolic phytochemical extracted from the Curcuma longa rhizome, whose chemical structure was reported in 1910.³¹⁻³⁷ Turmeric has been used in traditional Indian and South Asian medicine for approximately 2000 years and is recognized as a safe food ingredient by the U.S. Food and Drug Administration.^31,34 In 1876, the first report of the beneficial effect of turmeric flower demonstrated its efficacy against gonorrhea.³⁸ Since then, a plethora of studies have advocated the immense potential of turmeric against various chronic diseases. Since the period of Ayurveda (1900 B.C.), it has been used to treat skin diseases, respiratory disorders, and gastrointestinal disorders, as well as aches, pains, wounds, sprains, and liver malfunctions. Moreover, it is considered an effective way to expel worms, bacteria, and fungus and helps with dysbiosis. The active component curcumin exhibits countless pharmacological benefits owing to its anti-inflammatory, antimutagenic, antioxidant, antimicrobial, immunoregulatory, chemopreventive, and chemotherapeutic properties.^39,40 Curcumin, recognized as a potent anti-inflammatory agent, is well known for its capacity to scavenge reactive oxygen radicals, which are linked to inflammation. Curcumin is also believed to have an abrogating function in the pathophysiology of chronic disorders by regulating potent signaling molecules and enzymes.⁴¹⁻⁴⁴ Reports have shown that curcumin, demethoxycurcumin, and bisdemethoxycurcumin have no toxicity even at a dosage of 12,000 mg/day.⁴⁵ The antibacterial activity of curcumin was first reported in 1949, when it was demonstrated that the unsaturated ketones present in curcumin inhibit the growth of Staphylococcus aureus.⁴⁶ Curcumin is also antitumor in a number of biological signaling pathways, including phosphatidylinositol-3 kinase/Akt (PI3K/Akt), Janus kinase/Signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinase (MAPK), Wnt/-catenin, p53, nuclear factor kappa B (NF-κB), and apoptosis-related signaling pathways.⁴⁷⁻⁴⁹ Curcumin can prevent tumor growth, angiogenesis, epithelial–mesenchymal transition, invasion, and metastasis by modulating the expression of tumor-related non-coding RNA (ncRNA). It is now well known that gut dysbiosis is a primary cause of the initiation and development of many chronic diseases. Recent reports also suggest curcumin plays a crucial role in regulating the gut microbiota via biotransformation of curcumin and its metabolites.⁵⁰ These exceptional biological activities pose great advantages to the development of curcumin-based therapies for chronic diseases.^40,51−53

Despite its pleiotropic biological effects, one of the primary drawbacks of taking curcumin alone is its low bioavailability, which appears to be caused by poor absorption, fast metabolism, and excretion. Several compounds have been used to try to enhance curcumin’s bioavailability by addressing these various mechanisms, most of which are intended to block its metabolism. However, the low bioavailability issues appear to be overcome by including bioavailability-enhancing compounds such as piperine in curcumin formulations.^1,54−58 Curcumin intake has repeatedly been claimed to have anti-inflammatory and anticancer properties, as well as enhancing human health and illness prevention.^51,59 Curcumin has been thoroughly investigated and tested with >19,000 PubMed citations and >400 clinical studies for various chronic illnesses. It is already associated with a large body of literature supporting its utility as a powerful anti-inflammatory, antivirus, antioxidant, antibiotic, antigrowth, anti-atherotic, antidepressant, anti-arthritic, and wound-healing compound.^{29,55,60−62} Due to its tremendous potential as a therapeutic agent, it has been tested in human clinical trials for the prevention and treatment of several chronic diseases. This review focuses on the use of curcumin and turmeric in these clinical studies and their mechanisms of action. The therapies are reviewed in-depth for each disease. We further address how turmeric and curcumin, alone or in combination with other natural products, modulate a variety of molecular targets in order to provide in-depth insight into the molecular-level effects of treatment.

1. Composition of Turmeric

Turmeric (C. longa L.) is a rhizomatous herbaceous perennial herb that grows to 60–90 cm, is classified as a member of the Zingiberaceae family,⁶³ and is recognized as the most extensively investigated species of the genus Curcuma. It is highly rich in phytochemicals, giving it a wide range of biological activities (Figure 1). The major component of the root is a volatile oil consisting of turmerone and various other coloring compounds called curcuminoids, which are natural antioxidants, including curcumin, demethoxycurcumin, 5′-methoxycurcumin, and dihydrocurcumin. Turmeric in its standard form consists of volatile oils (<3.5%), molds (<3%), extraneous matter (<0.5% by weight), curcumin (5%–6.6%), and moisture (>9%). Other ingredients in the volatile oils include borneol, cinol, d-α-phellandrene, d-sabinene, sesquiterpenes, and zingiberene. The sesquiterpenes comprise numerous active components, such as germacrone; termerone; ar-(+)-, α-, and β-termerones; β-bisabolene; α-curcumene; zingiberene; β-sesquiphellanderene; bisacurone; curcumenone; dehydrocurdione; procurcumadiol; bis-acumol; curcumenol; isoprocurcumenol; epiprocurcumenol; procurcumenol; zedoaronediol; and curlone.⁶⁴ Turmeric also contains non-curcuminoids, such as turmerones, elemenes, bisacurone, curdione, bisabolones, curzerene, furanodiene, ferulic acid, coumaric acid, myristicin, cyclocurcumin, germacrone, curcumol, and calebin A, among many others. Curcumin (77%) is the most common curcuminoid, followed by demethoxycurcumin (18%) and bisdemethoxycurcumin (5%).⁶⁵

Figure 1.

Chemical structures of different constituents of turmeric.

In 2011, Li et al. identified at least 235 compounds, primarily phenolics and terpenoids, including 22 diarylheptanoids and diarylpentanoids, 8 phenylpropene and other phenolic compounds, 68 monoterpenes, 109 sesquiterpenes, 5 diterpenes, 3 triterpenoids, 4 sterols, 2 alkaloids, and 14 other compounds.³² Turmeric contains alkaloids, saponins, tannins, sterols, phytic acid, flavonoids, and phenols.⁶⁶ The turmeric plant also contains thiamine, riboflavin, niacin, calcium, phosphorus, potassium, and iron.⁶⁷ In 2008, Chowdhury et al. discovered 54 chemicals in turmeric from Bangladesh, including ar-turmerone (27.78%), α-Turmerone (17.16%), culone (13.82%), 2-carene (4.78%), zingiberene (4.37%), and sesquiphellandrene (5.57%).⁶⁸ According to Singh et al., essential oil from C. longa rhizome obtained in Orissa (India) contains turmerone (49.1%), β-phellandrene (5.3%), ar-curcumene (3.5%), eucalyptol (2.6%), and β-sesquiphellandrene (1.8%).⁶⁹ Stanojevic et al. reported that the total oil composition of turmeric from Turkey includes 65.4% oxygenated sesquiterpenes, the major components being turmerone, ar-turmerone, and curlone, followed by 8% benzene derivatives and 9.5% sesquiterpene hydrocarbons.⁷⁰

2. Chemistry of Curcumin

Curcumin (C₂₁H₂₀O₆) is a symmetric molecule with IUPAC name (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione and a molecular weight of 368.38. Its melting point is 184–186 °C. Curcumin exhibits maximum absorption (λ) at 429 nm. It comprises two aromatic rings with o-methoxy phenolic groups connected by an α,β-unsaturated β-diketone moiety.⁷¹ In the crystal state, it exists in a cis-enol configuration stabilized by resonance-assisted hydrogen bonding. In solution, it exists as cis–trans isomers, where the trans form is slightly more stable than the cis form. Curcumin is a hydrophobic molecule with a logP value of approximately 3.0 and a dipole moment of 10.77 D in its ground state. It is readily soluble in polar solvents like acetonitrile, chloroform, DMSO, ethyl acetate, ethanol, and methanol and is almost insoluble in water. One diketone moiety and two phenolic groups serve as the major reactive functional groups of curcumin. The biological activity of curcumin is tightly coordinated by hydrogen donation reactions, nucleophilic addition reactions, degradation, enzymatic reactions, and hydrolysis. Condensation/addition reactions are used to prepare chemically modified curcumin derivatives. Several of these derivatives have been found to be potentially cytotoxic to cancer cells when compared to free curcumin. This showcases the overall antitumor properties of curcumin.⁷²

3. Molecular Targets of Turmeric and Curcumin

Curcumin impacts a variety of molecular targets and signaling pathways, thereby increasing the efficiency of existing chemotherapeutic medicines (Figure 2). Curcumin is an efficient inducer of hemoxygenase-1 and a powerful inhibitor of reactive oxygen-generating enzymes, such as cyclooxygenase (COX), inducible nitric oxygen synthase (iNOS), lipoxygenase, and xanthine dehydrogenase/oxidase. Curcumin is also a powerful inhibitor of protein kinase C (PKC), tyrosine kinase, epidermal growth factor receptor (EGFR), and IB kinase. It suppresses NF-κB activation and the expression of oncogenes, such as c-jun, c-fos, c-myc, Akt, PI3K, cyclin-dependent kinase (CDK), ETS domain-containing protein-like (ELK), MAPK, mammalian target of rapamycin kinase (mTOR), NF-κB inducing kinase, and iNOS. PKC and the EGFR tyrosine kinase are thought to be the primary upstream molecular targets for curcumin action, but the nuclear oncogenes may function as downstream molecular targets. Curcumin inhibits tumor growth by inhibiting signal transduction pathways in target cells.^73,74 Continuous supplementation with nanocurcumin (two 40 mg capsules/day after a meal) for 3 months suppressed expression of inflammatory tumor necrosis factor-alpha (TNF-α), high sensitive protein with C-reactive protein (CRP), and interleukin-6 (IL-6) in a study of 80 obese patients with non-alcoholic fatty liver disease (NAFLD).⁷⁵

Figure 2.

Molecular targets of curcumin.

Other research on obesity/overweight individuals yielded the same results; in particular, 8 weeks therapy with curcumin (1 g/day) decreased blood levels of TNF-α, IL-6, and monocyte chemoattractant protein 1 (MCP-1) in men and women diagnosed with placebo metabolic syndrome (MetS).⁷⁶ In a randomized placebo-controlled trial of 60 teenaged females on a 10-week modest weight-loss diet, curcumin consumption (500 mg/day) produced a substantial reduction in hs-CRP and IL-6.^77,78 Curcumin also regulated circulating levels of IL-1 in patients who received curcumin (1 g/day) for 4 weeks. Conversely, concentrations of IL-6 and MCP-1 showed no remarkable differences.⁷⁹

Curcumin therapy in obese mice reduced NF-κB activity in liver tissue and reduced the hepatic production of TNF and MCP-1. Curcumin-treated animals also showed less macrophage infiltration, greater expression of forkhead transcription factor (Foxo)1 and adiponectin in adipose tissue (AT), and higher circulating adiponectin levels.⁸⁰ In addition, oral curcumin in male rats with high-fat diet (HFD)–type 2 diabetes mellitus (T2D) insulin resistance led to improved insulin sensitivity by lowering TNF blood levels.⁸¹ Furthermore, dietary curcumin (4 g/kg diet added twice weekly) mitigated the inflammatory response generated by the HFD in mice by suppressing NF-κB expression and the c-Jun N-terminal kinase (JNK) signaling pathway in the epididymal AT.⁸² It is remarkable that 0.1% curcumin (Curcuma-P) intake along with white pepper substantially reduced pro-inflammatory cytokines IL-6 and TNF-α, but did not alter IL-1 beta (IL-1β) and MCP-1 in the subcutaneous AT of mice after 4 weeks of HFD. This was a tissue-specific impact independent of macrophage invasion; however, Curcuma-P supplementation had no effect on inflammatory cell infiltration in AT.⁸³ According to research in various cell systems, the anti-inflammatory action of curcumin appears to be mediated by NLRP3 inflammatory regulation. Curcumin (6.25, 12.5, and 25 μM) remarkably reduced phorbol 12-myristate 13-acetate (PMA)-induced NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes, activation of caspase-1, and secretion of IL-1β by suppressing the TLR4/NF-κB pathway in THP-1 macrophages in vitro.⁸⁴ Curcumin inhibited cell migration and invasion by suppressing matrix metalloproteinase 9 (MMP-9) expression via downregulation of PKC/MAPKs and the NF-κB/activator protein 1 (AP-1) axis.^85,86In vivo studies of a breast cancer xenograft model showed that curcumin suppressed metastasis to the lung by suppressing NF-κB, MMP-9, COX-2, and vascular endothelial growth factor (VEGF) expression.^86,87 Therefore, curcumin impacts various signaling pathways that are deregulated in cancer and represents a potentially more potent and broad approach in cancer therapeutics.

Curcumin remarkably inhibits JAK/STAT signaling by downregulating pro-inflammatory interleukins, such as IL-1, IL-2, IL-6, IL-8, IL-12, and MCP-1. It promotes apoptosis and ER stress by targeting phosphorylated protein kinase-like ER-resident kinase, phosphorylated eukaryotic initiation factor-2α, glucose-regulated protein-78, caspase-4, and CCAAT/enhancer-binding protein (C/EBP) homologous proteins.^88,89 Curcumin also influences inflammatory responses by suppressing STAT3 activation and subsequent nuclear translocation by inhibiting lipoxygenase and xanthine oxidase activity.⁹⁰⁻⁹² Additionally, curcumin stifles the differentiation and development of Th17 cells by downregulating IL-1β, IL-6, IL-23, transforming growth factor beta (TGF-β), and STAT3 phosphorylation and inhibits tumor cell growth by targeting cyclin D1, c-myc, B cell lymphoma 2 (Bcl-2), B cell lymphoma 2-like protein (Bcl-xL), cellular FLICE inhibitory protein (cFLIP), X-linked inhibitor of apoptosis, and cellular inhibitor of apoptosis protein 1 (cIAP1), caspase-8, -3, and -9, and tumor suppressor genes, such as p53, p21, death receptor genes (DR4, DR5), and many cell signal pathways, including JNK, protein kinase B (PKB), also known as Akt, and several adenosine monophosphate-activated protein kinases (AMPK).^93,94 The potent anti-inflammatory effect of curcumin is hypothesized to be due to its ability to activate peroxisome proliferator activated receptor gamma (PPAR-γ).⁹⁵ The expression of nuclear factors erythroid 2-related factor (Nrf2) and heme oxygenase 1 (HO-1) is boosted by curcumin. Nrf2 binds to the nuclear factor-erythroid-derived 2 (NF-E2) binding sites, mediating a critical mechanism of protection against free radicals.⁹⁶ Curcumin also inhibits the key enzyme acetylcholinesterase (AChE) and p300, a positive regulator of the Wnt/β-catenin pathway.^97,98 Curcumin has also been suggested to prevent and cure neurotoxicity by replenishing dopamine and 3,4-dihydroxyphenylacetic acid levels.⁹⁹ This golden compound remarkably lowers blood glucose levels and improves insulin resistance by reducing hepatic glucose synthesis, inhibiting inflammatory reactions produced by hyperglycemia, boosting glucose transporters 2 (GLUT2), 3 (GLUT3), and 4 (GLUT4) gene expression, enhancing glucose uptake, and activating the AMPK signaling pathway. As a result, curcumin is recognized as a strong antihyperglycemic and promoter of insulin sensitivity.¹⁰⁰

4. Clinical Trials of Turmeric and Curcumin

Numerous preclinical and clinical studies have demonstrated that curcumin, derived from turmeric, is safe, well tolerated, and effective in preventing and treating a wide range of chronic diseases such as cancer, cardiovascular, metabolic, neurological, skin, hepatic, and infectious disorders (Table 1, Table 2, and Figure 3). Therefore, growing evidence favors turmeric as a broadly useful remedy for preventing and treating different diseases.

Table 1. Effects of Turmeric on Healthy Subjects and Various Diseases in Humans^a.

Disease/Condition	Turmeric Formulation	No. of Patients	Dose	Duration	Effects	Refs
Healthy Subjects
Aged volunteers	Turmeric root extract	16	10 g	Single dose	↑O2Hb, ↑tHb	(106)
Male runners	C. longa extract capsule	36	3 × 500 mg/day	30 days	↑Plasma curcumin concentration, ↑IL-10, ↓myoglobin	(108)
Male volunteers	Curcuma extract	18	6 g	Single dose	↓Hepcidin, ↑ferritin	(109)
	Turmeric matrix formulation	15	500 mg	Single dose	↑Absorption	(126)
	Turmeric powder	14	400 mg of curcumin	Single dose	↑Plasma concentration of curcuminoids	(125)
	Grated turmeric root	14	400 mg of curcumin	Single dose	↑Plasma concentration of curcuminoids	(125)
Premenopausal women	Botanical supplement	40	4 × 2 × 100 mg/day	12 weeks	↓Serum dehydroepiandrosterone, ↓DHEAS, ↓androstenedione, ↓estrone-sulfate	(110)
Older adults	Biocurcumax (BCM-95)	96	1500 mg/day	12 months	Stable MoCA score	(107)
Volunteers	Turmeric oil capsule	9	0.6–1 mL/day	3 months	No significant effects, well tolerated	(102)
	Turmeric extract tablet	207	1–2 tablets	8 weeks	↓IBS prevalence, ↓abdominal pain/discomfort score, improved IBSQOL	(111)
	NT supplement	24	6–12 g/day	12 weeks	No significant effects	(134)
	NT supplement	105	300–600 mg/day	24 weeks	Well tolerated	(103)
	Turmeric capsule	11	7 × 400 mg/day	8 weeks	↑Urinary oxalate, ↑oxalate/creatinine ratio, ↑net oxalate excretion and absorption	(138)
	Turmeric extract tablet	10	6 tabs	Single dose	No significant effects, well tolerated	(140)
	BCM-95 CG	11	4 × 500 mg	Single dose	↑Bioavailability	(104)
	Turmeric curry	8	0.5 g	Single dose	↑Breath hydrogen, ↓SBTT	(114)
	Turmeric tablet	7	6 × 0.4 g	–	↑Geranylgeranoic acid bioavailability	(119)
	Capsule	14	15 × 400 mg	Single dose	↑Serum insulin response, ↑insulin	(115)
	Fermented turmeric powder	48	0.75 mg–1 g (normalized to curcumin)	12 weeks	Safe and well tolerated	(131)
	C. longa extract	–	100 μg/mL	–	↓Formation of DOR and 3-MM from DEX, ↑DEX/DOR ratio	(117)
	Turmeric	25	500 mg	3 weeks	↓Platelet aggregation	(122)
	Infla-kine	24	2 capsules/day	4 weeks	↓IL-8, IL-6, NF-κB, TNF-α	(123)
	Turmeric tablets	30	2 tabs/day	4 weeks	↓TEWL	(124)
	Turmeric + caffeine + garlic	31	2698 mg	Single dose	↑PWV, SBP, DBP, VR, ↓large arterial elasticity	(137)
	Polyphenol-rich curry meal	17	6, 12 g	Single dose	↑Cinnamic acid, phenylacetic acid	(120)
	Turmeric extract + digoxin	12	1000 mg/day + 0.5 mg	7 days	↑Plasma concentration of digoxin	(121)
	WEC	47	–	8 week	↑Water content of the face	(185)
	Turmeric-based beverage	12	Single dose with MF breakfast	–	↑Serum CA, ↑UDCA, ↑CDCA	(118)
			Single dose with HF breakfast		↓DCA
	WEC tablet	90	900 mg/day	12 weeks	↓CRP, ↓TNF-α, ↓IL-6, ↓s-VCAM-1, ↓glucose, ↓HbA1c, ↓TG, ↑HDL-C, improved SF-36 and POMS scores	(601)
	Turmeric beverage	12	220 mL	Single dose	No significant effect on appetite sensation	(136)
	Turmacin capsule	90	0.5–1 g/day	12 weeks	↓Joint discomfort, ↓pain scores, ↑knee ROM, ↑mean of peak force	(113)
	Rhuleave-K softgels	88	2 × 500 mg/day	7 days	↓MSK pain, ↓unpleasantness and emotional aspects	(112)
	C. longa powder	12	1.5–6 g	Single dose	Low dose induced higher antioxidant capacity	(116)
	PUREMERIC	12	1000 mg/day	90 days	Safe, tolerable and no hepatotoxicity	(132)
	Actbiome	30	500 mg/day	8 weeks	↓GSRS, IL-10, ↑improvement in gut health	(175)
	NR-INF-02	48	1000, 2000 mg	84 days	Safe and tolerable	(105)
	Turmeric extract	24	1900 mg	Single dose	No safety issues observed	(191)
Healthy adults with chronic knee pain	Turmeric formulation (WDTE60N)	96	250 mg/day	90 days	↓VAS score, time taken for walk test TNF-α	(130)
Women volunteers	Turmeric	10	2.8 g	Single dose	No significant effects	(135)
Autoimmune Disorders
Rheumatoid arthritis	Turmeric matrix formulation	24	250, 500 mg/day	90 days	↓VAS, DAS-28, ESR, CRP, swollen joints, RF	(202)
Cancer
Breast cancer	San Huang decoction	30	10 g/day	1 day prior to surgery and 7 days postsurgery	↓Drainage of fluid, ↓average symptom score, ↓wound inflammation score, ↓CRP, ↓IL-2R, ↓IL-6, ↓IL-8, ↓TNF-α	(244)
	Turmeric formulation	39	3 capsules/day	5 ± 2 days	Free curcumin detected in breast tissues	(245)
Cancer anorexia	Turmeric + ginger	17	1 g + 1 g	14 days	↓Tolerability, ↑Toxicity	(246)
Cancer patients	Turmeric powder + diet	20	1 tsp	3 weeks	Improved antioxidant and/or anticoagulant activity	(230)
CML	Turmeric powder + Imitanib	–	–	6 weeks	↓NO levels	(255)
CRC	Curcuma extract	15	440–2200 mg/day	4 months	Well tolerated	(257)
	Curcuma extract	15	2 × 220 mg, 4 × 220 mg, 6 × 220 mg, 8 × 220 mg, 10 × 220 mg	29 days	↓PGE2	(256)
HNC-induced mucositis	BCM-95	–	500 mg	4 weeks	↓Incidence and severity of radiation	(273)
	Turmeric oral gel	–	1 g turmeric powder	37.5 ± 11.5 days	↓Pain score, ↑pain relief	(274)
Gastric cancer	Turmeric	–	1000 mg/day	5 days	↓Her2 levels	(266)
Prostate cancer	Zyflamed	29	780 mg/day	18 months	↓PSA, ↓CRP, ↓NF-κB	(311)
	Polyphenol tablet	203	3 × 100 mg/day	6 months	↓Percentage rise in PSA	(313)
	Phytotherapy tabletsb	22	400 mg/day	12 weeks	Well tolerated	(314)
	PROSTAFLOG	50	500 mg/day	30 days	↓PSA value	(312)
	Curcumin + turmeric oil	45	2 g/day + 228 mg/day	1 week before RT & until completion	↓Urinate frequency, sleeplessness, hurry to get to toilet, limitation in daily activity, unintentional release of urine	(315)
Gastrointestinal Disorders
Gut dysbiosis	Turmeric juice	28	3 × 2.5 g/week	12 weeks	↓pCS	(434)
IBS	Turmeric extract tablet	207	1–2 tablet/day	8 weeks	↓IBS prevalence, ↓abdominal pain and discomfort, improvement in symptoms	(111)
	Ayurvedic herbal preparation	32	2 × 100 mL/day	4 weeks	No significant effects	(439)
	CBP	67	500 mg	30 days	↓Abdominal bloating	(436)
PDS	C. longa capsule	78	750–1500 mg/day	4 weeks	↓FD, ↑recurrence rate	(435)
Peptic ulcer	C. longa capsule	25	5 × 600 mg/day	4 weeks	↓Ulcers, ↓abdominal pain and discomfort	(437)
Gynecological Conditions
PDM	Turmeric capsule	128	500 mg/day	5 days	↓Menstrual pain	(357)
Infectious Diseases
Helicobacter pylori infection	Turmeric tablet	36	3 × 700 mg/day	6 weeks	No significant effects	(392)
COVID-19 infections	Ayurcov (AyurCoro3)	120	3 × orally	1 day	↑Symptom relief, ↓resolution of symptoms in mild to moderate category, ↓rRT-PCR Ct values, improved functional status	(368)
			2 × gargle
Tinea corporis	Antimicrobial soap	30	–	4 weeks	↓Erythema, scaling, desquamation	(393)
Inflammatory Diseases
Asthma	C. longa capsule	55	2 × 30 mg/kg/day	6 months	↓Frequency of symptoms, ↓use of SaβAA, ↑disease control	(398)
Chronic hemodialysis	Turmeric	71	500 mg/day	12 weeks	↓hs-CRP, IL-6, TNF-α, ↑Albumin	(399)
Primary sclerosis cholangitis	Curcumin	15	2 × (750 mg/day)	12 weeks	↓ALP	(480)
Osteoarthritis	Herbomineral formulation	42	–	3 months	↓Severity of pain, ↓disability score	(417)
	C. domestica extract	107	4 × 500 mg/day	6 weeks	↓Time spent on the 100-m walk and stairs, ↓pain score	(413)
	CB formulation	30	2 × 500 mg cap/day	12 weeks	Improved pain score, walking distance, crepitus, ROM, ↓joint line tenderness	(412)
	NR-INF-02	120	2 × 500 mg/day	42 days	↓VAS score, WOMAC score, CGIC score, ↑tolerability	(415)
	C. domestica extract	367	1500 mg/day	4 weeks	↓WOMAC score	(408)
	AINAT capsule	42	2 or 3 × 650 mg cap/day	60 days	↓VAS, pain score	(411)
	C. longa extract	160	500 mg/day	120 days	↓VASP, ↓WOMAC, ↓IL-1β, ↓ROS, ↓MDA	(410)
	C. longa extract	367	1500 mg/day	4 weeks	↓WOMAC score	(400)
	LI73014F2	105	200–400 mg/day	90 days	↓WOMAC, ↑pain relief, ↑physical activity, ↑QoL	(409)
	Curene	50	500 mg/day		↓WOMAC score, VAS score	(416)
	Curamed	179	333 mg × 3/day	12 weeks	Well tolerated, ↓pain	(404)
	BCL	150	2 × 2 or 2 × 3 caps/day (46.6 mg/cap)	90 days	↓PGADA, ↓sColl2-1, ↓KOOS, ↓VASP	(418)
	BCM-95	74	3 × 500 mg/day	28 days	↓Pain, body weight	(465)
	C. longa extract capsule	70	2 capsules/day	12 weeks	↓VASP, ↓WOMAC pain	(407)
	Turmeric extract	60	Twice/day	4 weeks	↓PGE2	(414)
	BCM-95 capsule	193	2 × 500 mg/day	6 weeks	↓WOMAC pain and function/stiffness score, ↓CRP, ↓TNF-α	(405)
	C. longa capsules	24	2 × 500 mg/day	30 days	↓Means of Total WOMAC and VASP, ↑resistin, ↓adiponectin, ↓leptin, ↓sTNFR2	(406)
Metabolic Disorders
Dyslipidemia	Turmeric-based diet	113	–	6 months	↓LDL-C	(553)
MetS	Turmeric capsule	250	1.5–2.4 g/day	8 weeks	↓Weight, ↓hip circumference, ↓LDL-C, ↓cholesterol, ↓CRP, ↓TG, ↓BMI, ↓BF%, ↓FBG, ↑HDL-C	(554)
	Kepar pills	78	160 mg/day	4 months	↓BMI, waist circumference, TC, FBG body weight,	(555)
Hyperlipidemia	C. longa alcoholic extract	30	40 drops	3 months	↓TG, ↓TC, ↓LDL, ↓VLDL, ↑HDL	(557)
Hyperlipidemic T2D	Turmeric, Turmeric + Aerobic training	42	2100 mg/day	8 weeks	↓WC, ↓FBG, ↓hs-CRP, ↓TG, ↓SBP, ↓DBP, ↓MetS Z-score, ↓hs-CRP, ↓MDA, ↑GSH, ↑HDL, ↑TAC	(556)
NAFLD	Turmeric capsule	46	6 × 500 mg/day	12 weeks	↓Glucose, ↓insulin, ↓HOMA-IR, ↓leptin	(577)
	Turmeric	46	3 g/day	12 weeks	↓Homocysteine, ↓glucose, ↓insulin ↓HOMA-IR, ↓fetuin-A	(573)
	Turmeric	92	3 g/day	12 weeks	↓BMI	(575)
	Turmeric + chicory seeds		3 g/day + 9 g/day	12 weeks	↓MDA, ↓IL-6, ↑TAC	(575)
	Turmeric supplement	92	3 g/day	12 weeks	↓BMI, ↓WC, ↓ALP, ↑HDL-C, ↓TG/HDL-C, ↓LDL-C/HDL-C	(576)
	Turmeric	64	2 g/day	8 weeks	↓AST, ↓ALT, ↓GGT, ↓LDL, ↓HDL,	(574)
	Curcumin	27	3 × 500 mg/day	12 wks	↓Hepatic fibrosis, cholesterol, glucose, ALT, anthropometric indices, lipid profile, insulin resistance, hepatic statuses	(584)
Obesity	Spices including turmeric	20	14.5 g	Single dose	↓TG	(598)
	LI85008F	140	2 × 450 mg/day	16 weeks	↓Weight, ↓BMI, ↓waist and hip circumferences, ↓waist/hip ratio, ↓LDL-C, ↑HDL-C, ↓LDL/HDL ratio	(597)
	C. longa extract capsule	90	2 caps/day	12 weeks	↓Weight, ↓BMI, ↓CRP, ↓C3 levels, ↓AH score, ↑MH score	(599)
Overweight/obese women	Turmeric supplement	64	2.8 g/day	4 weeks	No significant effects	(596)
	Turmeric extract	60	500 mg/day	10 weeks	↓BMI, ↓Waist circumference, ↓Hip circumference, ↓TG/HDL ratio, ↑HDL, ↑Insulin	(78)
Obese young adults	Dietary intervention including turmeric	81	–	24 weeks	↓Body weight, visceral adipose tissue, glucose, TG, TC	(600)
prediabetes	Turmeric capsule	48	1 g	Single dose	Improved working memory	(13)
	Nutraceutical formulation	40	2 × 125 mg/day	10 weeks	↓TG, ↑HDL-C, ↓FPI, ↓HOMA-index	(524)
T2D	Turmeric extract + garlic extract	–	200 mg + 200 mg	12 weeks	↓FBS, ↓PP, ↓HbA1C, ↓TG, ↓TC, ↓LDL, ↓BMI, ↑HDL	(525)
	G-400	89	∼10 mg/day	8 weeks	↓FBG, ↓postprandial sugar, ↓HbA1c, ↑hemoglobin, ↓total cholesterol, ↓LDL-C, ↓TG, ↑HDL-C, ↓LDL-C/HDL-C	(522)
	C. longa	136	400 mg/day	12 weeks	↓Carotid-femoral pulse wave velocity, ↓left brachial-ankle pulse wave velocity, ↓aortic augmentation pressure and index, ↓arterial stiffness	(526)
	Turmeric capsules	80	3 × 700 mg/day	8 weeks	↓BMI, ↓glucose level, ↓HbA1c, ↓insulin, ↓HOMA-IR, ↓TG, ↓LDL-C, ↓total cholesterol	(523)
	Turmeric oil + curcumin	53	114 mg + 1500 mg	10 weeks	↓Weight, ↓BMI, ↓WC, FBS	(544)
	Galena capsule	71	500 mg/day	120 days	↓FVG, ↓HbA1c, ↓TG, ↓LDL-C, ↓SBP, ↓DBP, ↓HOMA-IR	(520)
	Turmeric capsule	89	500 mg/day	4 months	↓Neck circumference, ↓HbA1c, ↓HOMA-IR, ↓VLDL, ↓TG, ↓non-HDL-C	(521)
T2D nephropathy	Turmeric capsule	40	3 × 500 mg/day	2 months	↓Proteinuria, ↓IL-8, ↓TGF-β	(527)
Neurological Disorders
Fibromyalgia	Turmeric-based supplement + diet	13	500 mg	1 month	↓Intensity of symptoms	(618)
Ophthalmic disorders	Ophthacare eye drop	100	2 drops × 4	15 days	Safe and well tolerated	(425)
Oral Diseases
Gingivitis	Turmeric mouthwash	100	10 mg/mL	21 days	↓Plaque index, total microbial count	(670)
	Turmeric mouthwash	60	0.1%	21 days	↓Plaque index, ↓gingival index, ↓BAPNA	(667)
	Turmeric gel	150	–	21 days	↓Plaque index, ↓BAPNA	(669)
Chronic periodontitis	Turmeric chip	1	–	3 months	↓PI, ↓GI, ↓PPD, ↑RAL	(666)
Oral mucositis	Turmeric mouthwash	80	∼1200 mg/day	7 weeks	Delayed onset of mucositis	(280)
	Turmeric	60	–	–	Improved OMAS score	(281)
	BTF capsules	60	1–1.5 g/day	6 weeks	↓Incidence of grade 3 toxicity of oral mucositis, oral pain, dysphagia, and dermatitis, ↓weight loss	(279)
OSMF	Turmeric + pepper	40	2 × 400 mg/day + 2 × 100 mg/day	3 months	↑Mouth opening, ↓burning sensation, ↑SOD	(276)
	Turmix tablet	119	2 tablets/day	12 weeks	↑Mouth opening, tongue protrusion, ↓burning sensation	(277)
	Turmix tablet + turmix mouthwash	119	3 tablets/day + 2 times/day	12 weeks	↑Mouth opening, tongue protrusion, ↓burning sensation	(277)
	TurmNova	80	3 times/day	3 months	Safe, ↑Plasma curcumin levels	(278)
Psychological Disorders
Depression	BCM-95	52	1 g/day	8 weeks	Improved mood-related symptoms	(662)
Renal Disorders
ESRD	Turmeric capsule	50	3 × 500 mg/day	8 weeks	↓MDA, ↑RBC CAT activity, ↑albumin, ↓oxidative stress	(509)
CIN	Turmeric capsule	132	500 mg	Single dose	No significant effects	(508)
CKD	CB supplement	16	–	8 weeks	Improved IL-6 level	(505)
	Turmeric	101	320 mg/day	8 weeks	↑Attenuation of lipid peroxidation, antioxidant capacity	(506)
	Turmeric + orange juice + carrot	31	2.5 g + 100 mL + 12 g	3 months (after each HD)	↓NF-κB, hs-CRP	(504)
RLN	Turmeric capsule	24	3 × 500 mg/day	3 months	↓Proteinuria, ↓hematuria, ↓SBP	(511)
Skin Diseases
Eczema	Herbal formulation	360	–	–	↓Semiquantitative scores of erythema and edema, ↓itching, ↓scaling and lichenification	(703)
	Harbavate cream	150	2 times/day	4 weeks	↓Symptom score	(708)
Facial redness	Turmeric tablets	33	4 × 500 mg/day	4 weeks	↓Facial redness intensity and distribution	(706)
Hand-foot syndrome	Alpha	46	Twice daily	4 consecutive courses	↓Occurrence of the syndrome	(267)
Plaque psoriasis	Turmeric micromulgel	34	Twice/day	9 weeks	85% of the patients were happy	(214)
Psoriasis	Curcuma extract tablets	21	6 × 100 mg twice/week	2 months	↓PASI score, ↓BSA score	(212)
	Turmeric tonic	40	Twice/day	9 weeks	↓Erythema, ↓PASI score, ↑QoL	(210)
Psoriasis	Starch-fortified turmeric bath	60	2:1 (rice:turmeric)	10 days	↓Psoriasis area, ↓severity	(213)
Radiodermatitis	VTC	50	5 × 2 g/day	9 weeks	↓Appearance of dermatitis	(275)
Uremic pruritus	Turmeric capsule	100	3 × 500 mg/day	8 weeks	↓hs-CRP, ↓pruritus score	(510)
Miscellaneous
ATT-induced hepatotoxicity	Herbal formulation	528	6 g/day	4 months	↓Incidence of hepatotoxicity, ↓AST, ↓ALT, ↓bilirubin, ↓sputum-positive cases, ↓incidence of poorly resolved parenchymal lesion, improved patient compliance	(718)
Diarrhea	Turmeric + loperamide	136	3 × 500 mg + 10 mg	2 weeks	↓Reconsultation rate, ↓constipation	(719)
	Turmeric + berberine + loperamide		3 × 500 mg + 400 mg + 10 mg
Joint pain	Instaflex	108	50 mg/day	8 weeks	↓Joint pain severity, ↓WOMAC total and pain, stiffness, and function of knee joint	(402)
	TamaFlex	90	250–400 mg/day	90 days	↑SMWD, ↑SMWT, ↓time taken in SCT, ↓VASP, ↓WOMAC, ↑ primary knee flexion	(401)
	B-Turmactive	68	500 mg/day	1 week	↓Joint pain, ↓hs-CRP	(403)
Postprandial inflammation	HFCM	12	0.35–1.05 g	Single dose	↑CD14+/HLA-DR+ monocytes, ↓IL-1β	(507)
Pruritus in pregnant women	Turmeric oil + lavender essential oil + essential turmeric oil + peppermint oil	42	–	14 days	↓Pruritus	(704)
Patients who underwent SSP repair surgery	Tendisulfur	100	2 sachets for 15 days, 1 sachet for next 45 days	2 months	↓Pain score	(720)
Tendinopathy	C. longa extract + Boswellia extract	670	4 × 89 mg + 4 × 120 mg	1 month	↓Pain score, ↓motion limitation score, ↑patient satisfaction	(721)
Women who underwent Caesarean	Turmeric cream	180	–	14 days	↓REEDA score, edema	(705)

^aSymbols and abbreviations: ↑, Increase/Upregulation; ↓, Decrease/Downregulation; NR, Not reported; 3-MM, 3-methoxymorphinan; AH, Anger-hostility; ALP, Alkaline phosphatase; AUC, Area under curve; BCL, Bio-optimized Curcuma longa; BF%, Body fat percentage; BMI, Body mass index; BSA, Body surface area affected; C3, Complement component 3; CA, Cholic acid; CB, Curcuma longa and Boswellia serrata extracts; CBP, Curcumin Boswellia Phytosome; CD, Cluster of differentiation; CDCA, Chenodeoxycholic acid ; CIN, Contrast Induced Nephropathy; CKD, Chronic kidney disease; CML, Chronic myelogenous leukemia; CRP, C-reactive protein; DBP, Diastolic blood pressure; DCA, Deoxycholic acid; DEX, Dextromethorphan; DOR, Dextrorphan; ESRD, End-stage renal disease; FBG, Fasting blood glucose; FPI, Fasting plasma insulin; FVG, Fast venous glucose; GI, Gingival index; HbA1c, Hemoglobin A1c; HDL-C, High-density lipoprotein-cholesterol; HF, High fat; HFCM, High-saturated-fat, high-carbohydrate meal; HLA-DR, Human leukocyte antigen, DR isotype; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; IBS, Irritable bowel syndrome; IBSQOL, Irritable Bowel Syndrome Quality of Life; IL, Interleukin; KOOS, Knee injury and Osteoarthritis Outcome Score; LDL-C, Low-density lipoprotein-cholesterol; MDA, Malondialdehyde; MetS, Metabolic syndrome; MF, Medium fat; MH, Mental health; MSK, Musculoskeletal; NAFLD, Non-alcoholic fatty liver disease; NO, Nitric oxide; NT, Number Ten; O₂Hb, Cerebral oxygenated hemoglobin; OMAS, Oral Mucositis Assessment Scale (OMAS); PASI, Psoriasis Area & Severity Index; pCS, p-Cresyl sulfate; PDM, Primary dysmenorrhea; PDS, Postprandial distress syndrome; PGADA, Patient Global Assessment of Disease Activity; PI, Plaque index; POMS, Profile of Mood States; PPD, Probing pocket depth; RAL, Relative attachment level; RLN, Refractory lupus nephritis; ROM, Range of movement; SAβAA, short-acting β-adrenergic agonists; SBD, Small bowel dysbiosis; SBP, Systolic blood pressure; SBTT, Small-bowel transit time; s-Coll2-1, Serum levels of Coll2-1; SCT, Stair climb test; SF-36, MOS 36-item short-form health survey; SMWD, Six-minute walk distance; SMWT, Six-minute walk time; SOD, Superoxide dismutase; SSP, Supraspinatus; sTNFR1/2, soluble TNF-α receptors 1/2; T2D, Type 2 diabetes; s-VCAM-1, soluble vascular cell adhesion molecule-1; TEWL, Transepidermal water loss; TG, Triglycerides; tHb, Total hemoglobin; TNF-α, Tumor necrosis factor-alpha; UDCA, Ursodeoxycholic acids ; VASP, Visual Analog Scale of Pain; VLDL, Very-low-density lipoprotein; VTC, Vicco turmeric cream; WC, Waist circumference; WEC, Water extract of C. longa; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Table 2. Effects of Curcumin on Healthy Subjects and Various Diseases in Humans^a.

Disease/Condition	Curcumin Formulation	No. of Patients	Dose	Duration	Effects	Refs
Healthy Subjects
Aged adults	Theracur	40	2 × 90 mg/day	18 months	Improved SRT, visual memory attention, ↓neurodegeneration	(167)
	CurcuRouge	39	90 mg/capsule	4 weeks	↓WBC count, neutrophil count, Neutrophil/lymphocyte	(168)
	Cureit	30	500 mg	3 months	↓Time taken to walk the same distance, ↑Handgrip strength, weight-lifting capacity, distance covered	(169)
Healthy young males	HydroCurc + maltodextrin	28	500 mg + 500 mg	Single dose	↓Capillary lactate dehydrogenase	(180)
Healthy and moderately active	Cureit	30	500 mg	Single dose	↓CK, VAS score, DOMS occurrence, ↑VO2 max	(177)
Healthy older people	Lipidated curcumin (Longvida)	80	400 mg/day	12 weeks	↓Fatigue score, ↑blood glucose, working memory, mood	(178)
Healthy subjects, non-obese	Curcumin + resveratrol + tea extract + pomegranate extract + quercetin + acetyl-l-carnitine + lipoic acid + sesamin + cinnamon bark + fish oil	56	900 mg + 100 mg + 800 mg 250 mg + 650 mg + 500 mg + 600 mg + 1 g + 1.7 g + 1 g	6 months	No significant effect on metabolic and cardiovascular functions	(194)
Recreationally active males and females	Curcumin + piperine	23	2 g/day + 20 mg/day	11 days	↓Ubiquitin, MAFbx/atrogin-1, chymotrypsin-like protease, ↑DOMS time	(179)
Untrained college-aged subjects	Curcumin + fenugreek soluble fiber	47	190 mg/day + 300 mg/day	28 days	↑Neuromuscular fatigue threshold	(181)
Firefighters	Curcumin + heat	10	3 × 500 mg/dose	prior to exercise	↑GSH	(183)
Firefighters and military personnel	Curcumin	14	1500 mg/day	4 days	No significant effect	(184)
Fertile women with regular menstrual cycle	Encapsulated curcumin	80	800 mg	10 days	↓VEGF, ↑COX-2	(190)
Postmenopausal women	Theracurmin	51	150 mg/day	8 weeks	↑Carotid arterial compliance	(187)
	Theracurmin + exercise
	Curcumin	89	2 × 500 mg/day	8 weeks	↓Number of hot flashes	(186)
	Nanocurcumin	30	80 mg	6 months	↑miRNA-21	(188)
	Nanocurcumin + Nigella sativa oil	30	80 mg + 1000 mg	6 months	↑miRNA-21
	Curcumin	81	2 × 500 mg/day	8 weeks	↓MDA, hs-CRP, ↑TAC	(189)
	Curcumin	14	0.4 g	4 trial visits	Reduced bioavailability compared to turmeric powder	(125)
	Cur+	24	250, 500 mg	Single dose (3 times with 2 washout periods)	↑Bioavailability, no safety issues	(191)
Healthy volunteers	Curcumin + piperine	8	2 g+ 20 mg/kg	Single dose	Safe, ↑biovailability	(139)
	Curcumin powder	14	30 mg	Single dose	↑Bioavailability	(144)
	Theracurmin	14	30 mg	Single dose	↓Acetaldehyde, ↑bioavailability, alcohol intoxication	(144)
	Curcuminoid + piperine	8	16 g + 96 mg	2 days	No significant effect on paracetamol metabolization	(151)
	Curcumin powder	12	323 mg	Single dose	↑Absorption and bioavailability	(145)
	CLDM	12	64.6 mg	Single dose (14 day period)	↑Absorption and bioavailability	(145)
	Curcumin	18	5 g	–	↓Cardiovascular risk	(157)
	C3 complex	24	500–12,000 mg	–	Safe and tolerable	(45)
	C3 complex	12	10 and 12 g	0.25 to 72 h, single dose	↑Absorption	(150)
	CNTMF	45	500 mg	Single dose	No adverse effect, ↑bioavailability	(126)
	Curcumin capsule (with volatile oil)	45	500 mg	Single dose	No adverse effect, ↑bioavailability	(126)
	Curcumin capsule (phospholipid and cellulose)	45	500 mg	Single dose	↑Bioavailability	(126)
	Theracurmin	9	182.4 ± 1.0 mg/7 days	–	↑Absorption	(149)
	Meriva	9	152.5 ± 20.3 mg/7 days	–	↑Absorption	(149)
	Curcumin	11	4 × 500 mg	–	↑Absorption	(148)
	Curcumin (lecithin-piperine)	11	2000 mg	–	↑Bioavailability, retention time	(148)
	Theracurmin	6	150 and 210 mg	24 h	↑Bioavailability	(146)
	C3 complex	15	8 g	24 h	↑Metabolites in urine	(158)
	Curcumin	8	2 g	–	↑Sulphasalazine concentration, ↓BCRP	(164)
	Curcumin capsule	11	2 × 500 mg/day	2 weeks	↓Oxidative stress, inflammation, TNF-α, NF-κB	(163)
	Curcuminoids	24	500 mg/day	7 days	Effective, ↑antioxidant capacity, cholesterol, triglycerides	(162)
	Curcuminoids	24	6 g/day	7 days	Effective, ↑antioxidant capacity	(162)
	Curcumin (CP)	12	376 mg	–	Safe and well tolerated	(128)
	Curcumin (CHC)	12	376 mg	–	Safe and well tolerated	(128)
	Curcumin	12	1800 mg	–	Safe and well tolerated	(128)
	C3 extract	12	2920 mg (curcumin)/ day	6 days	↑Absorption	(147)
	Meriva	12	2 g/day	6 days	↑Absorption	(147)
	C3 complex + Bioperine	10	12 g + 60 mg	–	Safe, No significant effect	(155)
	Curcuminoids	38	4 g/day	30 days	No significant effect on UGT	(159)
	Curcumin-loaded NLC	15	0.5% w/w	4 weeks	↓Hydration, NMF, urea, ↑TEWL skin penetration	(171)
	Curcumin (Meriva)	8	500 mg/day	3 days	↓TLR4	(172)
	Curcumin	16	180 mg	4 days/week	↓PPBS, postprandial insulin	(173)
	Curcumin + fish oil	16	180 mg + 2 capsules	4 days/week	↓PPBS, postprandial insulin	(173)
	Curcumin	10	180 mg/day	7 days before exercise	↓IL-8, inflammation	(176)
	Curcumin	10	180 mg/day	7 days after	↓Muscle soreness, CK activity ↑MVC torque, ROM	(176)
	Cavacurcumin + ω-3 FA + astaxanthin + GLA + tocotrienols + hydroxytyrosol + vitamin D3 + potassium	80	500 mg + 675 mg + 3 mg + 9.5 mg + 12.5 mg + 6.25 mg + 1000 IU + 12.75 mg	4 weeks	↓IL-6, hs-CRP, SBP	(174)
	WEC + curcumin	47	30 mg	8 weeks	↑H2O content of the skin	(185)
	Curcumin + ferrous sulfate	155	500 mg + 18 or 65 mg of iron	Single dose	↑Serum ion, TIBC, Hb, serum transferrin saturation, ↓UIBC	(152)
	Curcumin + asafetida (Actbiome)	30	2 × 250 mg/day	8 weeks	↓IL-10, GSRS score, stool frequency	(175)
	Iron + curcumin	155	18 mg + 500 mg/day	6 weeks	↑TBARS	(192)
			65 mg + 500 mg/day		↓TNF-α
	Curcumin + piperine	16	500 mg/day + 5 mg/day	7 days	↓IL-2, TNF-α, INF, IL-6, IL-10	(193)
	Curcumin	18	2 × 500 mg/day	30 days	↓Audio-reaction time, choice-based visual reaction time, ↑Memory improvement	(182)
	Curcumin + galactomannan	18	2 × 500 mg/day	30 days	↓α/β ratio, audio-reaction time, choice-based visual reaction time	(182)
					↑α- and β-waves of EEG, memory improvement
					↑Fecal bifidobacteria, lactobacilli
Middle-aged people	Longvida	38	80 mg/day	4 weeks	↓TG, salivary amylase, Aβ protein, ICAM, ALT, ↑plasma catalase, MPO, plasma NO, scavenged radicals	(156)
	Curcumin capsules (with talinolol)	18	1000 mg/day	14 days	↑Plasma talinolol concentration	(161)
	Meriva	9	209 and 376 mg	–	↑Absorption	(59)
	Curcuminoid micelle	42	294 mg/day	6 weeks	Safe and highly bioavailable	(154)
	Curcumin (with talinolol)	12	300 mg/day	6 days	↓Bioavailibility of talinolol	(160)
	Curcumin	12	1800 mg	–	↑Absorption	(141)
	Curcumin (CW8)	12	376 mg	–	↑Absorption	(141)
	Curcumin phytosome formulation (CSL)	12	376 mg	–	↑Absorption	(141)
	Curcumin (CEO)	12	376 mg	–	↑Absorption	(141)
	Curcumin drink (Thera curmin)	24	30 mg/100 mL	–	↑Absorption efficiency	(142)
Autoimmune Diseases
Ankylosing spondylitis	Nanocurcumin	24	80 mg/day	4 months	↓RORγt, IL-17, miR-141, miR-155, miR-200	(201)
	Nanocurcumin	24	80 mg/kg	4 months	↓miR-17, miR-27, Il-6, ↑Treg cells, miR-146a, FOXP3, IL-10, TGF-β2	(420)
Psoriasis	Curcumin	10	1% alcoholic gel	4 weeks	↓PhK activity, TRR, severity of parakeratosis, CD8+ T cells	(211)
	Meriva	63	2 g/day	12 weeks	Effective, ↓serum IL-22	(209)
	Nanocurcumin + acitretin	15	3 g/day + 0.4 mg/kg/day	12 weeks	↓PASI	(208)
Rheumatic arthritis	Acumin	36	2 x 250 mg/day,	3 months	Safe and well tolerated, ↓Pain, inflammation, swollen joints, tender joints	(202)
			2 x 500 mg/day
	Curcumin + ginger + black pepper	60	–	8 weeks	↓TJC, ESR, SJC, DAS score	(204)
	Nanocurcumin	10	20 mg/L, 50 mg/L	8 months	↓Inflammation	(207)
	Nanocurcumin	65	3 × 40 mg/day	12 weeks	↓DAS-28 score, TJC, SJC	(206)
RA with chronic periodontitis	Curcumin + essential oil	45	0.1% w/w	6 weeks	↓ESR, RF, CRP, ACPA, PI score, PD, CAL	(205)
Cancer
Benign prostatic hyperplasia	Curcumin + tamsulosin + finasteride	116	2.25 g/day + 0.2 g/day + 5 mg/day	6 months	↓Waist circumference, PPFT, PV IPSS-total, IPSS-V, IPSS-S	(317)
					↑Qmax, IIEF-5, QoL
Bladder	Nanocurcumin	26	180 mg/day	4 weeks	↑Clinical response	(241)
Brain tumor	Micellar curcumin	10	3 x 57.4 mg/day	4 days	↑Inorganic phosphate, bioavailability, ↓PCr/Pi	(243)
Breast	Curcumin (Docetaxel)	10	500–8000 mg/d	6 cycles (7 days	↑Antitumor activity each)	(250)
	Curcumin	30	6 g/day	Course of radiotherapy	↓Radiation-induced dermatitis	(252)
	C3 complex	686	3 × 2000 mg/day	RT and post RT	↓Reduced severity	(251)
	PureVida (curcumin + hydroxyl tyrosol + fish oil)	45	3 capsules/ day	30 days	↓CRP, pain score	(247)
	Curcumin + paclitaxel	150	300 mg/wk + 80 mg/m2	12 weeks	↑ORR, physical performance	(248)
	Curcumin gel	171	4%	1 week	↓Skin reactions, pain	(249)
Cervical	Curcumin + radiotherapy	40	4 g/day	7 days	↓Survivin levels	(253)
Colorectal	C3 capsule	15	450, 900, 1800, or 3600 mg/day (curcumin)	4 months	Well tolerated, no toxicity, ↓PGE2	(260)
	C3 capsule	12	450, 1,800, or 3600 mg/day (curcumin)	7 days	↓DNA adduct (M1G)	(261)
	Curcumin capsule	126	3 x 360 mg/day	10–30 days (prior surgery)	↑Body weight, ↓TNF-α, Bcl-2, ↑apoptotic cells, DNA fragmentation, p53, Bax	(262)
	Curcumin C3 complex	24	2.35 g/day	14 days	Safe, ↑glucoronide	(259)
	curcumin + FOLFOX + Bevacizumab	18	2 g/day		↑Overall survival, progression-free survival	(258)
CRLM	C3 complex	12	500 mg/day	7 days	Safe and tolerable	(263)
	Curcumin (FOLFOX)	12	500 mg, 1 or 2 g/day	1 week	Safe and tolerable, ↓ALDH, CD133	(263)
Cystic glandularis	Curcumin	14	50 mg	Once per week for 4 weeks and once per month for 2 months	↓Core lower urinary tract symptom score	(240)
FAP	Curcumin + quercetin	5	3 × 480 mg/day + 3 × 20 mg/day	6 months	↓Polyp number and size, ileal and rectal adenomas	(264)
HNC	Nanocurcumin	29	80 mg/day	6 weeks	↓OM severity, ↑OM development duration	(289)
HNC with oral mucositis	Curcumin + PBM-T + PDT	31	20 mL (1.5 g/L)/week	4 weeks	↓Healing time	(293)
	Nanocurcumin	74	0.1% (thrice daily for 7 days)	6 weeks (scored)	↓Risk of OM, severity, delayed onset	(295)
	Nanomicelle curcumin	50	2 × 80 mg/day	7 weeks	↓Pain score, severity	(296)
Oral mucositis	Zinc oxide + amla + tulsi + curcumin	75	1%	35 days	↓Disease severity	(298)
Hepatocellular carcinoma	Curcuminoids + piperine + taurine	20	4 g + 40 mg + 500 mg	30 days	↓IL-10, miR-21	(299)
Glioblastoma	Curcumin + propranolol + aliskiren + cilazapril + celecoxib + piperine + aspirin + metformin	10	–	10 weeks	↑Median survival	(270)
Malignant lesions	Curcumin	24	500–12,000 mg/day	3 months	↓Lesions, safe	(327)
Multiple myeloma	Curcuminoids	25	3600 mg /day	3 months	↓Random urinary protein, serum creatinine, uDPYD	(302)
	Curcuminoids	18	7200 × 2 mg/day	9 months	↓rFLC, total protein, random urinary protein, iFLC, dFLC, PTH, uDPYD	(302)
	Curcumin + melphalan + prednisone	33	8 g + 4 mg/m2 + 40 mg/m2	28 days	↓NF-κB, VEGF, TNF-α, IL-6	(304)
Neurofibromatosis 1	curcumin diet	11	1200 mg/day	6 months	↓Number and volume of cutaneous neurofibromas	(271)
Oral malignancy	Curcumin	60	950 mg/day	3 months	↓p53, Ki67, cyclin D1	(294)
	Curcumin + green tea extract	60	950 mg/day + 800 mg/day		↑Clinical response rate, ↑mouth opening
Pancreatic or biliary duct cancer	Bioavailable curcumin	16	200–400 mg/day	>9 months	No adverse effects	(305)
Pancreatic cancer	Curcumin	25	8 g/day	8 weeks	No toxicity, ↑IL-6, IL-8, IL-10, IL-1RA, ↓NF-κB, COX-2, p-STAT3	(307)
	Curcumin	17	8000 mg/day	4 weeks	↑Chemotherapeutic effect	(308)
	Curcumin	21	8 g/day	–	No toxicity, safe and feasible	(310)
	Curcumin	66	8 g/day	2 months	↓Lean body mass, survival of sarcopenic patients, ↑fat loss, muscle loss	(306)
	Phytosomal curcumin	44	4 × 500 mg/day	Until death	↑Response rate, stable disease period, progression-free survival, overall survival	(309)
Prostatic hyperplasia	Curcumin (Meriva)	61	2 × 200 mg/day (2 × 500 mg/day)	24 weeks	No side effects, ↑QoL, ↓signs and symptoms of disease, urinary infections, urinary block	(321)
Prostate cancer	Curcumin	45	3 g/day	1 week before radiotherapy until completion	↓Urinate frequency, hurry to get to toilet, sleeplessness, unintentional release of urine, limitation of daily activity, difficulty in going out	(315)
	Curcumin	26	6000 mg/day	7 consecutive days in each cycle (total 6 cycles)	Safe and well tolerated, no toxicity	(316)
	Nanocurcumin	64	120 mg/day	3 days before and during RT	↑Prevention of proctitis	(318)
	Curcumin	97	1440 mg/day	6 months	↓PSA	(319)
	Curcumin + docetaxel	50	6 g/day + 75 mg/m2/day	7 days/3 wks + 1 day/3 wks for 6 cycles	↓Progression-free survival and overall survival	(323)
	Curcumin + quercetin + hyaluronate + chondroitin sulfate	49	200 mg/day + 400 mg/day + 40 mg/day + 400 mg/day	12 weeks	Improved QoL, ↓urinary incontinence	(320)
Advanced metastatic tumors	Liposomal curcumin	32	100, 300 mg/m2	8 weeks	↓PSA, CEA, CA 19-9	(234)
Solid tumors	Meriva	80	180 mg/day	8 weeks	Safe and well tolerated, ↑QoL, ↓TNF-α, TGF-β, IL-6, IL-8, hs-CRP, CGRP, MCP-1, Sp	(233)
	Curcumin phosphatidylcholine + Irinotecan	10 DE, 13 PK	1, 2, 3, and 4 g/day + 200 mg/m2	28 days	↑Tolerability, no toxicity	(232)
Thyroid nodule (benign)	Curcumin, Boswellia, spirulina	39	2 × (50 mg, 50 mg, 400 mg)	12 weeks	↓Nodule area	(326)
Differentiated thyroid carcinoma	Nanocurcumin	21	160 mg/day	10 days	↓MN in lymphocyte	(325)
Cardiovascular Diseases
ACS	Curcumin	75	15 mg × 3/day, 30 mg × 3/day, 60 mg × 3/day	2 months	↓TC, LDL-C, ↑HDL-C, TG	(342)
Central arterial hemodynamics	Curcumin	45	150 mg/day	8 weeks	↓LV afterload, aortic SBP, aortic Aix	(331)
	Curcumin + exercise
Coronary artery bypass surgery	Curcuminoids capsule (+ standard therapy)	121	4 g/day	3 days before and 5 days after surgery	↓MI, CRP, MDA, NT-proBNP	(334)
Coronary artery disease	Curcumin	33	4 × 500 mg/day	8 weeks	↓TG, LDL-C, VLDL-C	(335)
	Nanomicelle curcumin	70	80 mg/day	3 months	↓MMP-9, MMP-2	(337)
Coronary heart disease	Curcumin	50	45 mg/day	7 days prior and 2 days after PCI	↓hs-CRP, sCD40L	(338)
Tetralogy of Fallot patients	Curcumin	45	45 mg/day	14 days	↓c-JNKe, caspase 3, temperature, better ventricular functions	(343)
Myocardial injury	Nanocurcumin	110	480 mg	Single dose	↓Raise of CK-MB PCI	(340)
Patients undergoing coronary elective angioplasty	Curcumin	90	500 mg/day	8 weeks	↓TC, TG, LDL-C, MDA, hs-CRP, TNF-α, ↑TAC, IL-1β, SOD, GPx	(341)
	Nanomicelle curcumin		80 mg	8 weeks
Takayasu arteritis	Curcumin	246	300 mg/day	4 weeks	↓BVAS score, ESR, TNF-α, CRP	(339)
Endothelial Function
Endothelial function	Curcumin (Longvida pill)	39	2000 mg/day	12 weeks	Safe and well tolerated, ↓oxidative stress, ↑resistance and conduit artery endothelial function	(345)
	Curcumin	32	150 mg/day	8 weeks	No adverse effect, ↓SBS, ↑FMD, VO2 peak	(346)
Gynecological Conditions
Cervical dysplasia	Curcumin	13	500, 1000, 1500, 2000 mg/day	14 days	Safe and tolerated	(351)
Endometriosis	Ialuril soft gel tablets	20	2 pills/day	12 weeks	↓Dysmenorrhea, chronic pelvic pain, dysuria	(362)
Laparoscopic gynecologic surgery	Curcuminoid extract	60	1 g/day	3 days	↓VAS score, pain severity	(364)
Laparoscopic hysterectomy	Curcuminoids	98	4 × 250 mg/day	3 days	↓VAS score, pain	(363)
PCOS	Curcumin	67	1500 mg/day	3 months	↑GPx activity, SOD, PGC-1α, SIRT1	(352)
	Curcumin	60	500 mg/day	12 weeks	↓Weight, BMI, FPG, insulin, insulin resistance, TC, LDL-C, ↑insulin sensitivity, HDL-C, PPARγ, LDLR	(353)
	Curcumin	30	93.34 mg (2 dose)	8 weeks	↓Body weight, body fat mass, waist circumference, FBG, insulin, HOMA-IR, TC, TG, CRP	(354)
	Curcumin	67	3 × 500 mg/day	12 weeks	↓FPG, dehydroepiandrosterone	(355)
Premenstrual syndrome	Curcumin	63	100 mg/12 h	3 menstrual cycles (10 days each)	↓Severity of behavioral, mood, physical symptoms, PMS severity, mood swings, ↑BDNF	(359)
	Curcumin	63	100 mg/12 h	10 days each for 3 cycles	↓PMS symptoms, ↑anti-inflammatory effect	(358)
Premenstrual syndrome and dysmenorrhea	Curcuminoids + piperine	124	500 mg + 5 mg	10 days each for 3 cycles	↓PSST score, dysmenorrhea pain	(360)
	Curcumin + piperine	76	500 mg + 5 mg	10 days/3 CMC	↓AST, bilirubin, ↑vitamin D	(361)
Infectious Diseases
COVID-19	Nanocurcumin	80	4 × 40 mg/day	14 days	↓mRNA and serum IL-6, mRNA and serum IL-1β	(369)
	Nanocurcumin	41	4 × 40 mg/day	2 weeks	↓Symptoms, ↑oxygen saturation, recovery	(371)
	Nanocurcumin	60	4 soft gels (40 mg each)/day	2 weeks	↓Symptoms, CRP, resolution time, ↑lymphocyte count	(370)
	Nanocurcumin	40	4 × 40 mg/day	2 weeks	↓IFNγ, TBX21, ↑TGF-β, IL-4, FOXP3	(372)
	Curcumin + piperine	140	2 × 525 mg + 2 × 2.5 mg	14 days	↓Deterioration, red flag signs, symptom severity, ↑oxygen saturation, better clinical outcome	(373)
	Nanocurcumin	80	2 × 80 mg/day	21 days	↑Treg cell frequency, FOXP3, IL-10, IL-35, TGF-β	(374)
	Nanocurcumin	80	2 × 80 mg/day	21 days	↓RORγt, IL-17, IL-21, IL-23, GM-CSF, Th17 cell count, fever, cough, dyspnea, mortality rate, ↑hospital discharge rate	(375)
	Nanocurcumin	48	160 mg/day	6 days	↑O2 saturation, ↓symptoms, LOS	(376)
	Nanocurcumin	60	240 mg/day	7 days	↓Mortality rate, IFNγ, TNFα, IL-1β, IL-6	(377)
	Curcumin + VCO + Azithromycin + Oseltamivir + hydroxychloroquine	60	3 g/day + 30 mL + 500 mg + 150 mg/day + 400 mg/day	21 days	↓ IL-1β, IL-2, IL-6, TNF-α, IFNβ	(378)
	ArtemiC (arteminisin 6 mg/mL, curcumin 20 mg/mL, frankincense 15 mg/mL, vitamin C 60 mg/mL)	50	2 × 20 mg/day (curcumin)	Days 1 and 2	↑Clinical improvement, SpO2 normalization, ↓O2 supplementation, fever, hospital stay	(379)
	Curcumin + piperine	46	2 × (500 mg + 5 mg)/day	14 days	↓weakness, dry cough, sore throat, sputum cough, ague, muscular pain, headache, dyspnea	(380)
HIV/AIDS	Curcumin	20	1000 mg/day	30 days	↑TG	(382)
HIV	Curcumin	20	1000 mg/day	30 days	No significant effect	(386)
AIDS	Curcumin + PDT	30	0.75 mg/mL + 20.1 J/cm2	once	↓CFU for Streptococcus and Staphylococcus	(384)
Peptic ulcer with H. pylori infection	Curcumin	40	3 × 500 mg		↓IL-1β, ↑healing efficacy, TAC	(396)
Sepsis	Nanocurcumin	40	2 × 80 mg	10 days	↓PCT, TNF-α, SOFA score, duration of ventilation	(383)
	Nanocurcumin	14	160 mg	10 days	↓ESR, IL-8, neutrophils, platelets, presepsin, WBCs, ↑lymphocyte count	(390)
	Nanocurcumin	40	2 × 80 mg/day	14 days	↓MDA, IL-18, IL-1β, ICAM-1, VCAM-1, IL-6, TLR4, Bax, FBS, TG, TC, ALT, ALP, GGT, bilirubin, creatinine, prealbumin, SOFA score, duration of ventilation ↑IL-10, CAT, SOD, TAC, Bcl-2, Nrf-2, TLC	(391)
Inflammatory Diseases
Behcet’s disease	Nanocurcumin	32	80 mg/day	8 weeks	↑Treg cells, RNAs of FOXP3, TGF-β, IL-10, miRNA-25, miRNA-106b	(421)
Bronchial asthma	Curcumin + standard therapy	77	2 × 500 mg/day	30 days	↓ESR, eosinophils, adverse events, ↑FEV1, weight gain	(422)
	Curcumin + piperine	40	2 × 750 mg/day + 5 mg/day	2 months	↓IL-6, ↑FEV1, FVC, ACT score	(423)
Crohn’s disease	Bioavailable curcumin	40	360 mg/day	12 weeks	↓Endoscopic disease severity, ↑clinical remission rate, anal lesion healing	(444)
	Curcumin	62	3 g/day	6 months	↓Recurrence rate	(445)
	Curcumin + azathioprine	48	3 g/day + 2.5 mg/kg/day	3 months	↑Fecal calprotectin	(446)
Dry eye syndrome	Curcumin + lutein + zeaxanthin + vitamin D3	59	200 mg + 20 mg + 4 mg + 600 IU	8 weeks	↓OSDI score, corneal and conjunctival staining score, tear osmolarity, MMP-9 positive score, SPEED score, ↑Schirmer’s strip wetness length, tear volume, TBUT score	(426)
Exercise-induced inflammation	Curcumin	24	180 mg/day	7 days before exercise and 2 days after exercise	↓Muscle soreness, ↑ROM	(717)
Exercise-induced oxidative stress and inflammation	Curcumin	20	3 × 500 mg/day	28 days	↓Muscle soreness, CK	(716)
Gastrointestinal damage	Curcumin	8	500 mg/day	3 days	↑Gastrointestinal function	(438)
Gall bladder function	Curcumin	12	20 mg single dose	1 week	↑Gall bladder contraction, ↓gall bladder volume	(431)
	Curcumin	12	20, 40 and 80 mg	1 week	↓Gall bladder volume, ↑gall bladder contraction	(433)
IBS	Curcumin	9	2 × 550 mg/day, 3 × 550 mg/day	1 month + 1 month	↓Abdominal pain and cramp, next 1-month muscle soreness, CDAI scores	(440)
	Curcumin (SZ or mesalamine)	82	2 g/day	6 months	Safe, ↓disease associated morbidity	(441)
	Curcumin	11	500 mg × 2/day	3 weeks	Well tolerated, ↑disease improvement	(443)
			1 g × 2/day	3rd–6th weeks
			2 g × 2/day	6th–9th weeks
	Curcumin (mesalamine)	50	3 g/day	1 month	Safe, no adverse event, ↑clinical improvement	(442)
	Curcuminoids (NCB-02 + oral 5-ASA)	30	140 mg/day	8 weeks	No side effects, better clinical response and outcomes	(448)
	Curcumin + fennel essential oil	116	84 mg/day + 50 mg/day	30 days	↓Severity score, abdominal pain, ↑symptom relief, QoL	(453)
Liver cirrhosis	Curcumin	60	1000 mg/day	3 months	↓ALP, bilirubin, MELD scores child-Pugh score	(427)
	Curcumin	58	1000 mg/day	12 weeks	↓LDSI 2.0 domain score, ↑CLDQ domain score, SF-36 domain score	(428)
Mastitis	Curcumin cream	63	3 × 200 mg/pump	3 days	↓Mastitis, tension, erythema, pain	(429)
Osteoarthritis	Curcumin (Meriva)	50	200 mg/day (1 g/day)	3 months	Effective, ↓joint pain, ↑joint function, stability, absorption	(455)
	Curcumin (Meriva)	100	200 mg/day (1 g/day)	8 months	↑Tolerable, physical performance, ↓sCD40L, IL-1β, IL-6, sVCAM-1, ESR, distal edema	(458)
	C3 complex	40	1500 mg/day	6 weeks	Effective and safe, ↓Pain, stiffness	(457)
	Theracurmin	50	180 mg/day	8 weeks	Improved outcomes, ↓Pain	(460)
	Curcunminoid + piperine	40	1500 mg/day + 15 mg/day	6 weeks	↓IL-4, IL-6, hs-CRP	(461)
	Flexofytol	20	252 mg/day	3 months	↓Coll2-1, CRP	(463)
	C3 complex	40	1500 mg/day	6 weeks	↑Anti-inflammatory effect, ↓IL-4, hs-CRP	(456)
	C3 complex + Bioperine	40	1500 mg/day + 15 mg/day	6 weeks	↑SOD, GSH, ↓MDA, oxidative stress	(462)
	Longvida	50	2 × 400 mg/day	90 days	↓VAS score, WOMAC score	(464)
	Nanomicelle curcumin	30	80 mg/day	3 months	↓VAS score, CRP, CD4+, CD8+, Th17 cells, B cells, ↑Treg cells	(466)
	Nanocurcumin	71	80 mg/day	6 weeks	↓Overall disease score, pain score, stiffness score, WOMAC score	(467)
	Curcumagalactomannoside + glucosamine hydrochloride	80	400 mg/day + 500 mg/day	84 days	↓VAS score, WOMAC score, stiffness score	(468)
	Curcumagalactomannoside	72	400 mg/day	6 weeks	↓VAS score, WOMAC score, stiffness score, ↑walking performance, physical function	(469)
	Curcumin ointment	72	5%, twice/day	6 weeks	↓Mean knee pain intensity	(470)
	Curcumin ointment	72	5%	6 weeks	↑QoL score	(471)
	Curcumin + BSE + PBE + MSM	106	168 mg/day + 250 mg/day + 100 mg/day + 1500 mg/day	12 weeks	↓Activity impairment, FIHOA score	(472)
	Nanocurcumin	15	80 mg/day	3 months	↓miRNA 155, miRNA 138, miRNA16	(473)
	Curcumin + meloxicam	42	1600 mg/day + 15 mg/day	12 weeks	↓Pain, IL-1β, IL-6, TNF-α, ↑physical function	(474)
Osteochondral diseases	Curcumin (Theracurmin)	23	180 mg/day	12 months	↓Roughness in lateral compartment of femur, stiffness of knee joint, ↑JOA score, VAS, JKOM	(475)
Osteo-muscular pain	Algocur	50	1 g	10 days	↓Pain, impaired physical functions, safe and tolerable	(477)
Pancreatitis	Curcumin (piperine)	20	500 mg (5 mg)	6 weeks	↓Erythrocyte MDA, ↑GSH	(478)
Chronic SM-induced cutaneous complications	C3 complex + Bioperine	96	1 g/day + 10 mg/day	4 weeks	↓Inflammation, serum IL-8, CGRP, hs-CRP, pruritus score	(710)
Pain and fatigue after cholecystectomy	Curcumin	50	500 mg/6 h	–	↓Pain, fatigue	(479)
Pruritus	C3 complex + Bioperine	96	1 g/day + 10 mg/day	4 weeks	↓Sp, SOD, GPx, CAT, ↓DLQI score, disease severity; safe	(711)
Prostate biopsy	Curcumin (with soy isoflavones)	85	100 mg (40 mg)	6 months	↑Anti-androgen effects, ↓PSA	(486)
CP/CPPS	Curcumin + Calendula extract	48	350 mg + 80 mg,	1 month	Well tolerated, ↓pain, inflammatory cytokines, inflammatory cells	(487)
			1 suppository/day
RAS	Curcumin gel	57	2%	2 week	↓Pain intensity, ulcer size	(483)
	Nanomicelle-Cur gel	48	3 × 1%/day	1 week	↓Lesion size, pain score	(481)
	Cur gel	48	3 × 2%/day	1 week	↓Lesion size, pain score
	Curcumin gel	48	2%	180 days	↓Erythema, pain score, ulcer size recurrence	(482)
	Curcumin orabase	58	3 × 5%	10 days	No significant effect	(484)
Rhinitis	Curcumin capsule	241	500 mg/day	2 months	↓Nasal symptoms, sneezing, itching, rhinorrhea, IL-4, IL-8, TNF-α, ↑IL-10, sICAM-1	(485)
Third molar postsurgical acute inflammation	Curcumin	90	3 × 200 mg/day	-	↓Pain	(419)
Ulcerative colitis	Curcuminoids nanomicelles	56	3 × 80 mg/day	4 weeks	↓Score for urgency of defecation, SCCAI score	(449)
	Curcumin + green tea + selenium	20	1000 mg/day + 500 mg/day + 200 μg/day	8 weeks	↑Improvement rate, remission rate	(450)
	Curcumin	70	1500 mg/day	8 weeks	↓ESR, hs-CRP, ↑QoL	(451)
	Bioenhanced curcumin	69	2 × 50 mg/day	6 weeks	↑Remission rate, clinical response sustained remission	(452)
Inherited Disorders
Familial adenomatous polyposis	Curcumin	44	2 × 1500 mg/day	12 months	No effect	(489)
Colorectal adenomatous polyposis	Phospholipidated curcumin + Mirtoselect	35	500 mg + 500 mg	4–6 weeks	↓NF-κB, Ki-67	(490)
DMD, FSHD, LGMD	FLOVOMEGA	29	80 g/day	24 weeks	↓CK levels, ↑walking distance	(491)
β-Thalassemia/HbE	Curcuminoid	21	500 mg/day	12 months	↓MHb, H2O2-induced MDA, SOD GPx, NTBI, ↑GSH	(492)
	Curcuminoids + NAC + DFP	50	500 mg/day + 200 mg/day + 50 mg/kg/day	12 months	↓Iron load, oxidative stress, blood coagulation, ↑antioxidant potential	(493)
	Curcuminoids	10	500 mg/day	12 months	↓Apo-A1, ↑vitronectin, PON1, apo E, prothrombin	(496)
	Curcuminoids	30	2 × 250 mg/day or 4 × 250 mg/day	24 weeks	↓Hypercoagulability, NTBI, ROS MDA, D-dimer, hs-CRP, TNF-α, TGF-β1, IFNγ, IL-1β, IL-6, IL-8, serum iron, transferrin saturation	(499)
β-Thalassemia intermedia/major	Curcumin	61	2 × 500 mg/day	12 weeks	↓MDA, direct bilirubin, ↑TAC, HB	(494)
	Curcumin	68	2 × 500 mg/day	12 weeks	↓NTBI, ALT, AST	(495)
	Curcumin	68	2 × 500 mg/day	12 weeks	↓HOMA-IR, TG, TG/HDL-C, hs-CRP	(497)
	Curcumin	30	3 × 500 mg/day	3 months	↓Copper, ferritin, BMI, TG, ↑zinc, zinc/copper ratio	(498)
	Curcumin	30	3 × 500 mg/day	3 months	↓Iron, ferritin, transferrin	(500)
Kidney Diseases
ADPKD	Curcumin + ascorbic acid	68	25 mg/kg/day + 0.075 g/kg	1 year	Improved FMDBA	(512)
CKD	Curcumin	60	3 × 500 mg/day	5 days	No significant effect	(518)
	Curcumin phytosome	24	2 × 500 mg/day	3 or 6 months	↓Carbohydrate intake, protein intake, total fiber intake, phosphorus and potassium intake MCP-1, IL-4, IFNγ, TBARS, PCS, Escherichia-Shigella, Enterobacter verrucomicrobia, Firmicutes, ↑Lachnoclostridium spp., Lachnospiraceae family, Lactobacillaceae spp., Prevotellaceae	(513)
DKD	Curcumin	14	500 mg/day	15–30 days	↓U-mAlb, LDL-C, plasma LPS, caspase 3, ↑NQO-1, SOD1, SOD2, gut microbiota, IκB	(514)
Hemodialysis	Curcumin + resveratrol	40	500 mg/day + 500 mg/day		↓Ferritin, TG, VLDL, %fat, ↑BMI, muscle and bone mass	(516)
	Curcuminoids	43	1 g/day	12 weeks	↑catalase activity, preserved GPx activity	(515)
	Nanocurcumin	54	120 mg/day	3 months	↓Serum IL-6 and TNF-α, mRNA IL-6 and TNF-α	(517)
Metabolic Disorders
Diabetes	Curcumin (NCB-02)	67	2 × 150 mg/day	8 weeks	↓MDA, ET-1, IL-6, TNF-α	(529)
	Curcuminoid capsule	237	6 × 250 mg/day	12 months	↑β-cells function, HOMA-β, adiponectin, ↓C-peptide, insulin resistance	(533)
	Curcuminoids extract	100	300 mg/day	3 months	↓fasting blood glucose, HbA1c, insulin resistance, FFAs, triglycerides, ↑LPL	(531)
	Curcumin + glyburide	8	475 mg/day + 5 mg	10 days	Beneficial in glycemic control, ↓LDL, VLDL, triglycerides, ↑HDL	(530)
	Curcuminoids	100	–	2 months	↓A-FABP, CRP, TNF-α, IL-6, FFAs, glucose, CRP, ↑SOD	(532)
	Curcuminoid	240	6 × 250 mg/day	6 months	↓pulse wave velocity, leptin, TG, HOMA-IR, uric acid, visceral fat, total body fat, ↑adiponectin	(534)
	Curcuminoids + piperine	118	1000 mg/day + 10 mg/day	12 weeks	↓TC, non-HDL-C, lipoprotein a, ↑HDL-C	(549)
	Curcuminoids + piperine	118	1000 mg/day + 10 mg/day	12 weeks	↓MDA, ↑TAC, SOD	(548)
	Curcuminoids + piperine	100	500 mg/day + 5 mg/day	3 months	↓glucose, C-peptide, HbA1c, ALT, AST	(537)
	Curcumin	44	3 × 500 mg/day	10 weeks	↓TG, hs-CRP, ↑adiponectin	(543)
	Curcumin	53	3 × 500 mg/day	10 weeks	↓Mean weight, BMI, WC, FBS	(544)
	Curcumin	40	80 mg/day	8 weeks	↓FBG, glycated Hb, insulin	(647)
	Curcumin + exercise	40	80 mg/day	8 weeks
Fasting dysglycemia	Curcumin + berberine extract + inositol + banaba extract + chromium picolinate	148	200 mg + 200 mg + 3000 mg + 40 mg + 100 μcg	3 months	↓FBS, PPBS, HbA1c, insulin, HOMA-index, TG, TC, hs-CRP	(535)
Hypercholesterolemia	Curcumin (Meriva) + Phytosterol	82	228 mg/day + 2.3 g/day	4 weeks	↓TC, LDL-C, TC:HDL-C ratio, CVD risk, LDL-P number	(536)
Hypermetabolic syndrome	Curcumin	120	1 g/day	6 weeks	↓Saturated fatty acid intake	(564)
	Phospholipidated curcumin	120	1 g/day	6 weeks
Non-insulin-dependent DM	Theracurmin	33	180 mg/day	6 months	↓TG, γ-GTP, no change-AT-LDL	(545)
T2D on hemodialysis	Nanocurcumin	60	80 mg/day	12 weeks	↓FPG, insulin, TG, TC, LDL-C, VLDL-C, TC/HDL-C, hs-CRP, MDA, ↑TAC, TN	(546)
T2D and CHD	Curcumin	60	1000 mg/day	12 weeks	↓PSQI, MDA, ↑TAC, GSH, PPARγ	(550)
Diabetic microangiopathy	Curcumin (Meriva)	50	1 g/day	4 weeks	Well tolerated, ↓skin flux, edema, ↑PO2	(551)
	Meriva + standard therapy	77	2 × 500 mg/day	4 weeks	Optimal tolerability, improved	(552)
Diabetic foot ulcer	Nanocurcumin	60	80 mg/day	12 weeks	↓FPG, insulin, TC, LDL-C, ↑insulin sensitivity, TAC, GSH	(547)
T2D-associated macular edema	Phospholipidated curcumin	11	2 × 500 mg/day	3 months	↓Macular edema, ocular thickness, ↑improvement, stable disease period	(538)
	Hydrophilic curcumin	73	2 capsules	6 months	↓Central retinal thickness	(539)
Risk of T2D	Curcumin	64	2 × 500 mg/day	12 weeks	↓TG, ↑insulin sensitivity	(540)
	Curcumin + LnC-3 PUFA	64	2 × 500 mg/day + 2 × 1000 mg/day FO	12 weeks	↓TG	(540)
	Curcumin (Meriva)	29	180 mg/day (2 × 500 mg/day)	12 weeks	↓GSK-3β, IAPP, insulin resistance, risk of Alzheimer’s disease	(541)
MetS	C3 complex + bioperine	100	1 g/day + 10 mg/day	8 weeks	Effective, ↓LDL-C, non-HDL-C, total cholesterol, triglycerides, Lp(a), ↑HDL-C	(562)
	C3 complex + bioperine	100	1 g/day + 10 mg/day	8 weeks	Safe and effective, ↑BMI, SOD, ↓hs-CRP, MDA, glucose, FBS, HbA1c, SBP, DBP	(561)
	C3 complex + bioperine	100	1 g/day + 10 mg	8 weeks	Safe and well tolerated, ↓TNF-α, IL-6, TGF-β, MCP-1	(76)
	C3 complex + bioperine	100	1 g/day + 10 mg/day	8 weeks	↑Adiponectin, ↓leptin	(558)
	Curcumin	120	1 g/day	6 weeks	↑Serum PAB	(170)
	Curcumin (phospholipid complex)	120	1 g/day	6 weeks	↑Serum PAB	(170)
	Curcumin	120	1 g/day	6 weeks	No effect on serum vitamin E	(560)
	Curcumin (lecithinized)	120	1 g/day	6 weeks	No effect on serum vitamin E	(560)
	Curcumin	120	1 g/day	6 weeks	↓Severity of anxiety	(571)
	Phospholipidated Curcumin	120	1 g/day	6 weeks	↓Severity of anxiety	(571)
	Curcumin	81	1 g/day	6 weeks	↑Aryl esterase activities	(563)
	Curcumin	120	1 g/day	6 weeks	↑Zn	(565)
	Phospholipidated curcumin	120	1 g/day	6 weeks	↑Zn	(565)
	Phosphatidylcholine curcumin	80	2 × 500 mg/day	6 weeks	No effect	(569)
	Nanocurcumin + aerobic exercise	44	80 mg/day	6 weeks	↓IL-6, MDA, hs-CRP, ↑IL-10, BDNF, TAC	(566)
	Nanocurcumin	50	80 mg/day	12 weeks	↓TG, HOMA-β	(567)
	Curcuminoids	109	1 g/day	6 weeks	No significant effect	(570)
	Phospholipidated curcuminoids	109	1 g/day	6 weeks	No significant effect	(570)
	Nanocurcumin	50	80 mg/day	12 weeks	↓MDA, ↑adiponectin, TAC	(568)
NAFLD	Curcumin	87	1000 mg/day	8 weeks	Safe and well tolerated, ↓total cholesterol, LDL-C, triglycerides, non-HDL-C, uric acid	(580)
	Curcumin formulation	80	500 mg/day	8 weeks	↓Liver fat content, BMI, TC, LDL-C, TG, AST, ALT, glucose glycated Hb	(579)
	Curcumin capsule (Meriva)	87	1000 mg/day	8 weeks	Safe and well tolerated, ↓BMI, AST, ALT, liver fat	(581)
	Curcumin	46	1.5 g/day	3 months	↓Fibrosis score	(582)
	Phospholipidated curcumin	36	1500 mg/day	8 weeks	↓Severity, BMI, TC, LDL-C, TG, HDL-C, non-HDL-C, uric acid, portal vein diameter, liver size, ↑hepatic vein flow	(583)
	Nanocurcumin	84	80 mg/day	3 months	↓Fatty liver degree, WC, liver transaminase, FBS, FBI, HbA1C, TG, TC, LDL, HOMA-IR, TNF-α, hs-CRP, IL-6, ↑HDL, QUICKI, nesfatin	(75)
	Phospholipid curcumin	58	250 mg/day	8 weeks	↓3-methyl-2-oxovaleric acid, 3-hydroxyisobutyrate, kynurenin, succinate, citrate, α-ketolgutarate, methylamine, trimethylamine, hippurate, indoxyl sulfate, chenodeoxy cholic acid, lithocholic acid, taurocholic acid	(585)
	Curcumin + piperine	24	500 mg/day + 5 mg/day	8 weeks	↓PAB	(587)
	Curcumin + piperine	70	500 mg/day + 5 mg/day	12 weeks	↓Hematocrit, ESR, AST, ALT, ALP, cholesterol, Fe, Hb, LDL, ↑TIBC	(586)
	Curcumin (Meriva)	65	250 mg/day	8 weeks	↓Leptin ↑HDL, adiponectin	(588)
	Curcumin	55	3 × 500 mg/day	12 weeks	↓Hepatic fibrosis, NF-κB	(589)
	Curcumin + fish oil + sunflower oil + silymarin + choline bitartrate + tocopherol	113	2 × 35 mg + 250 mg + 150 mg + 75 mg + 35 mg + 10 mg	3 months	↓ALT, AST, GGT	(590)
	Curcuminoids + piperine	55	500 mg/day	8 weeks	↓Weight, severity, TNF-α, MCP-1, EGF	(591)
	Curcumin (Meriva)	45	250 mg/day	8 weeks	↓Weight, waist circumference, hip circumference, waist/hip, BMI, percentage of m-MLH1 and m-MSH2	(592)
	Nanomicelle curcumin	45	80 mg/day	12 weeks	↓ALT, AST	(593)
	Nanomicelle curcumin + resistance training
	Curcumin	44	250 mg/day	8 weeks	↓CML, 8-OHdG, weight, waist circumference, body fat, BMI	(594)
Obesity	Curcuminoids + bioperine	30	1 g/day + 10 mg/day	30 days	↓TG	(603)
	Curcuminoids + Bioperine	30	1 g/day + 10 mg/day	10 weeks	↓Serum PAB	(604)
	Curcuminoids + bioperine	30	1000 mg/day + 10 mg/day	4 weeks	↑Zn/Cu ratio	(615)
	C3 Complex + bioperine	30	1 g/day + 5 mg/day	30 days	↓IL-1β, IL-4, VEGF	(79)
	Curcumin	40	500 mg/day	12 weeks	↓LDL, lipid peroxidation, oxLDL, protein carbonyls, ↑creatinine	(602)
	Curcumin	40	750 mg/day	12 weeks	↑Creatinine, ↓protein carbonyls	(602)
	Curcumin	60	500 mg	4 weeks	↓MCP-1, MIF	(614)
	CurQfen	22	500 mg/day	12 weeks	↓Homocysteine, ↑HDL	(609)
	Phytosomal curcumin	80	800 mg/day	8 weeks	↓FPG, FPI, HOMA-IR, GGT, GOT, GPT, LAP, HSI, FLI, TG, non-LDL-C, ↑HDL-C	(610)
	Curcumin	40	500 mg/day	8 weeks	↓Weight, BMI, FBG	(611)
	Curcumin + aerobic exercise				↓Waist circumference, HOMA-IR, waist-hip-ratio, insulin, LDL/HDL, TC/HDL, CRP, ↑HDL-C
Older adults with abdominal obesity	Curcumin + resveratrol	22	2 × 50 mg + 100 mg	Single dose	↓Postprandial VCAM1	(605)
Older adults with obesity	Curcumin (Longvida)	134	160 mg/day (800 mg/day)	16 weeks	↓SMCs, ↑vigor	(607)
	Curcumin + fish oil		160 mg/day + 2000 mg/day DHA + 400 mg/day EPA
	Curcumin (Longvida)	134	160 mg/day	16 weeks	↑CVR, improved memory test and verbal memory test	(606)
	Curcumin (Longvida) + fish oil
	Curcumin (Longvida)	126	160 mg/day (800 mg/day)	16 weeks	↓Cerebral artery stiffness, CRP	(608)
	Curcumin + fish oil		160 mg/day + 2000 mg DHA + 400 mg EPA		↑HDL-C, CRP
Obese adults	Curcumin (Longvida)	152	160 mg/day (800 mg/day)	16 weeks	No significant effect on arthritis	(476)
	Curcumin + fish oil	152	160 mg/day + 2000 mg DHA + 400 mg EPA	16 weeks
Obesity and prediabetic	Curcumin	82	500 mg/day	90 days	↓FPG, PPG, HbA1c, IR, insulin	(612)
	Curcumin + zinc		500 mg/day + 30 mg/day	90 days	↓BMI, FPG, PPG, HbA1c, IR, insulin
Obesity and prediabetes	Curcumin	82	500 mg/day	90 days	↓BMI, weight, TC, TG, LDL, non-HDL, ↑HDL	(613)
	Curcumin + zinc		500 mg/day + 30 mg/day	90 days
Osteoporosis	Curcumin + alendronate	60	110 mg/day + 5 mg/day	12 months	↑Osteocalcin, BMD, ↓BALP, CTx	(616)
Neurological Disorders
Alzheimer’s disease	Curcumin	8	2 × 20 g/day	2 days	↑Detection of amyloid spots in retina	(542)
	C3 complex	30	2 or 4 g/day	24 weeks	Well tolerated	(619)
Amyotrophic lateral sclerosis	Curcumin	42	600 mg/day	6 months	Stable score of ALS-FRS-r, FRAP ↓AOPPs, lactate	(620)
	Nanocurcumin	54	80 mg/day	12 months	↑Survival	(621)
Cognitive function	Curcumin (Longvida)	60	400 mg	1 and 3 h (4 weeks for chronic)	↑Attentive performance, memory tasks, ↓total cholesterol, LDL-c	(624)
Dementia	Curcumin (Theracurmin)	40	90 mg × 2/day	18 months	Improved memory, ↓amyloid, tau	(623)
DSS	Curcumin powder	1	50 mg/kg/day, 75 mg/kg/day	12 months (4 months + 8 months)	Safe and well tolerated, ↑QoL, knee flexion, foot strength, ↓hand and elbow strength, pulmonary function, hand function, upper/lower extremity	(622)
HAM/TSP	Curcumin	20	80 mg/day	12 weeks	↑c-FLIPL, c-FLIP	(625)
Ischemic stroke	Curcumin	42	2 × 750 mg/day	3 months	↑Muscle power, improvement in SSQL questionnaire specific domains, ↓SBP	(626)
ME/CFS	NAIOS	76	NR	15.2 ± 4.8 months	↓IgM-mediated autoimmune response to OSEs and NO-adducts, FF score, severity of illness	(642)
Migraine	Nanocurcumin	74	80 mg/day	2 months	↓Frequency of headache attack	(628)
	ω-3 FA + nanocurcumin		2500 mg/day + 80 mg/day		↓Frequency of headache attack, TNF-α
	Nanocurcumin	72	–	2 months	↓Frequency of headache attack, serum ICAM-1 levels	(627)
	ω-3 FA + nanocurcumin	72		2 months
	Nanocurcumin	80	80 mg/day	2 months	↓IL-6 mRNA, IL-6, hs-CRP	(630)
	ω-3 FA + nanocurcumin	80	2 × 2500 mg + 80 mg/day	2 months
	Nanocurcumin	74	80 mg/day	2 months	↓COX-2, frequency of attack, severity of pain	(631)
	ω-3 FA + nanocurcumin	74	1800 mg + 80 mg/day	2 months	↓COX-2, iNOS, frequency of attack, severity of pain, headache duration
	Nanocurcumin	38	80 mg	2 months	↓Pentraxin 3	(633)
	Nanocurcumin	40	80 mg	2 months	↓IL-17 mRNA, serum IL-17	(634)
	Nanocurcumin	100	80 mg/day	8 weeks	↓Frequency, severity, duration, HDR	(636)
	Nanocurcumin + coenzyme Q10	100	80 mg + 300 mg/day
	Nanocurcumin + ω-3 placebo	80	80 mg	2 months	↓VCAM	(632)
	Nanocurcumin + EPA + DHA + other ω-3	80	80 mg + 2 × 600 mg + 2 × 300 mg + 100 mg ω-3
	Nanocurcumin	74	80 mg/day	2 months	↓Attack frequency	(635)
	Nanocurcumin + ω-3 FA		80 mg/day + 2.5 g/day		↓Attack frequency, IL-1β
	Nanocurcumin	44	80 mg/day	2 months	↓MCP-1, headache attack frequency, headache severity and duration	(631)
Multiple sclerosis	Nanocurcumin	60	80 mg/day	6 months	↓Th17 cells, RORγt, IL-17	(638)
	Nanocurcumin	50	80 mg/day	6 months	↓miR-16, miR-17-92, miR-27, miR-29b, miR-126, miR-128, miR-132, miR-155, miR-326, miR-550, miR-340, demyelinating inflammatory condition, ↑miR-15a, miR-16, miR-19b, miR-106b, miR-320a, miR-363, miR-31, miR-181c, miR-150, miR-340, miR-599	(641)
	Nanocurcumin	50	80 mg/day	6 months	↑Frequency of T-reg cells, FoxP3, TGF-β, IL-10	(639)
Parkinson’s disease	Curcumin	60	80 mg/day	9 months	↓MDS-UPDRS part III score	(643)
Spinal cord injury	Curcumin + anti-inflammatory diet	20	1200 mg/day	3 months	↓Pro-inflammatory composite score, IFN-γ, CRP, IL-6, IL-1β, ↑TRP/LNAA ratio	(644)
	Curcumin	100	110 mg/kg/day	6 months	↑BMD indicators of lumbar, neck, and hip	(645)
T2D-associated neuropathy	Nanocurcumin	80	80 mg/day	8 weeks	↓HbA1c, FBS, total score of neuropathy, total reflex score, temperature	(646)
	Nanocurcumin	80	80 mg/day	8 weeks	↓Depression, anxiety	(648)
Traumatic brain injury	Curcuminoids + piperine	62	500 mg/day + 5 mg/day	7 days	↓Leptin	(649)
	Curcuminoids + piperine	62	500 mg/day + 5 mg/day	7 days	↓IL-6, TNF-α, MCP-1, CRP, SOFA score, NUTRIC score, APACHEII score	(650)
Psychotic Disorders
Depression	Curcumin	40	500 mg/day	5 weeks	No adverse effect, ↑relief	(665)
	Curcumin	60	1 g/day	6 weeks	Well tolerated, effective, and safe	(664)
	C3 complex	30	1 g/day	2 months	↓Anxiety	(659)
	Curcuminoids + piperine	111	1000 mg/day	6 weeks	Safe and effective, ↓anxiety,	(663)
	Curcumin powder	108	1000 mg/day	6 weeks	↓Inflammation, IL-1β, TNF-α, depressive symptoms, salivary cortisol, ↑BDNF	(661)
	Curcumin	123	250 mg × 2	12 weeks	No adverse effect, ↓depressive and anxiolytic symptoms	(660)
	Curcumin	123	500 mg × 2	12 weeks	No adverse effect, ↓depressive and anxiolytic symptoms	(660)
	Curcumin + saffron	123	250 mg × 2	12 weeks	No adverse effect, ↓depressive and anxiolytic symptoms	(660)
	Curcumin	65	500 to 1500 mg/day	12 weeks	Safe, and well tolerated, ↓depression, HAM-A in males, ↑HAM-A in females	(657)
Schizophrenia	Curcumin	12	180 mg/day	8 weeks	↓IL-6, hs-CRP, ↑working memory	(654)
Chronic schizophrenia	Curcumin	38	3000 mg/day	24 weeks	↓CDSS scores, ↑PANSS score	(655)
	Nanocurcumin	56	160 mg/day	16 weeks	↓PANSS negative subscale score, CGI-S, CGI-I, ↑PANSS positive subscale, response rate	(656)
Oral Diseases
Dental carries	Curcumin	18	1500 μg/mL	4 days	↓Microbial biofilm, ↓ microbial viability	(676)
	Curcumin (blue light)	18	1500 μg/mL	4 days	↓Microbial biofilm, ↓ microbial viability	(676)
Gingivitis	Curcumin mouth wash	30	–	21 days	Effective adjunct therapy	(681)
	Nanocurcumin	50	80 mg/day	4 weeks	↓MGI, PBI	(680)
Denture stomatitis	Chitosan curcuminoids	10	3 × 10 mL/day	2 weeks	↑Anti-candida activity, complete response (80%)	(389)
	Curcumin + photodynamic therapy	45	100,000 UI/mL	15 days	↓Overall CFU/mL score, ↓Candida albicans, C. tropicalis, C. glabrata	(388)
OLP	Curcumin tablet	20	2000 mg/day	4 weeks	No detectable effect	(290)
	C3 complex	33	2000 mg/day	7 weeks	Well tolerated	(672)
	C3 complex	53	500–6000 mg/day	1–5 year follow-up	↓Symptoms	(674)
	C3 complex	20	6000 mg/d	12 days	Well tolerated, efficacious, ↓signs and symptoms, erythema, ulceration	(673)
	C3 complex	20	2000 mg/day	4 weeks	Complete remission of lesions, ↓VAS score, Thongprasom score	(290)
	Curcumin	40	2000 mg/day	7 days	↓Lesion size, pain index, severity index	(291)
	Nanocurcumin gel + Triamcinolone chloride	31	1% + 0.1%	4 weeks	↓REU score, ↑Efficacy index	(292)
	Nanocurcumin	57	80 mg/day	1 month	↓Lesion size, pain, burning sensation	(297)
Oral mucositis	Curcumin mouth wash	7	10 drops × 2/day	21 days	No adverse effect, safe, and well tolerated	(675)
Orthodontic treatment	Curcumin (blue light)	55	1.5 mg/mL	4 consecutive times (1 week each)	No side effects, ↓plaque accumulation	(693)
Oral disinfection	Curcumin	13	1.5 g/L	Single dose	↓Bacterial population	(695)
	Curcumin (PDT)	13
	Curcumin (blue light)	24	1 g/L	Single dose	↓Bacterial survival and growth	(697)
	Curcuminb (SDS + blue light)	24
	Curcumin solution a	27	20 mL of 30 mg/L stock	1 and 2 h	↓Microbial growth	(694)
	Curcumin	50	25 and 100 mg/L	–	↓Effective, microbial growth	(698)
OSF	Longvida	30	2 g/day	3 months	↑Mouth opening, VAS score	(284)
	Curcumin	90	2 × 300 mg/day	6 months	↓Burning sensation, ↑Mouth opening flexibility, tongue protrusion, cheek flexibility	(283)
	Curcumin + piperine	147	3 × 300 mg +5 mg	12 weeks	↓Burning sensation, ↑mouth opening flexibility	(277)
	Curcumin + piperine + turmeric extract mouthwash	147	3 × 300 mg + 5 mg + 0.1% w/v 10 mL	12 weeks	↓Burning sensation, ↑mouth opening flexibility, tongue protrusion capacity	(277)
	Topical curcumin gel	120	1% (3 times/day)	6 weeks	↓Burning sensation, ↑mouth opening flexibility	(285)
	Topical curcumin gel + triamcinolone acetonide and hyaluronidase gel					(286)
	Curcumin gel	40	2% gel	4 weeks	↓Burning sensation, LDH, ↑mouth opening flexibility	(287)
	Curcumin mucoadhesive patch		2% curcumin	4 weeks	↓Burning sensation, LDH, ↑mouth opening flexibility
	Curcumin	30	500 mg/day	3 months	↓Burning sensation, ↑mouth opening	(288)
	curcumin + piperine	41	3 × 300 mg/day + 5 mg/day	12 weeks	↓Burning sensation, ↑mouth opening flexibility, better changes in color of mucosa	(286)
Periodontits	Curcumin gel	25	1%	6 months	↓Oral bacterial growth	(682)
	Curcumin strip + SRP	20	0.2%	21 days	↓PI, GI, SBI, PPD, ↑SOD	(686)
	Curcumin + SRP	10	2 mg gel	4 weeks	↓PPD, PI, ↑CAL gain	(687)
	Curcumin gel	25	2%	3 months	↓SBI, PPD, RAL, CFU	(685)
	Curcumin	23	1% solution	7, 14, 21 days	↓Bleeding score, plaque index score, probing pocket depth, BANA positive site	(684)
	Curcumin nanogel	45	2%	45 days	↓Aa, Pg, Tf, ↑antimicrobial effect	(688)
	Curcumin-loaded NPs	20	50 μg	15 days	↓Porphyromonas gingivalis PPD, CAL, BOP, IL-6, ↑Veillonella parvula, Actinomyces spp.	(683)
	Curcumin gel	15	–	30 days	↓Plaque index	(690)
	Curcumin	76	200 mg	7 days	↓Postoperative discomfort, pain	(692)
Postsurgical periodontitis	Curcumin mucoadhesive film	15	0.5%	1 week	↓Postsurgical pain, swelling, consumption of analgesics	(691)
Periodontitis (T2D)	SRP + curcumin	25	100 mg/mL	–	↓PPD, PI, ↑CAL gain	(689)
	SRP + curcumin + LED
Root canal obturation material	Curcumin	64	1 g	6 months	61.5% success rate	(679)
	Curcumin + calcium chloride				81.3% success rate
Pulmonary Disorders
COPD	Curcumin	39	2 × 90 mg/ day	24 weeks	↓AT-LDL	(700)
Pulmonary complications	C3 complex	78	1.5 g/day	4 weeks	Safe and well tolerated, ↓IL-6, IL-8, TNFα, TGFβ, MCP-1, Sp, hs-CRP, CGRP	(701)
	C3 complex	89	1.5 g/day	4 weeks	↓Serum MDA, ↑GSH, improved CpAT and SGRQ scores	(702)
Stress/Oxidative Stress
Occupational stress	CurQfen	60	500 mg × 2/day	30 days	↑QoL, antioxidant markers ↓stress, anxiety, and fatigue, lipid peroxidation, ↑Absorption, pharmacokinetics	(713)
	CurQfen	60	500 mg/day	30 days	↑Absorption, pharmacokinetics
Arsenic-induced oxidative stress	Curcumin capsules (with piperine)	286	1 g/day	3 months	↓DNA damage, ↓ROS generation, ↓lipid peroxidation, ↑antioxidant activity	(714)
Exercise-induced oxidative stress	Curcumin capsule	10	90 mg	2 h (before exercise)	↓d-ROMs, ↑BAP, GSH, CAT	(715)
	Curcumin capsule	10	90 mg × 2	2 h (before and after exercise)	↓d-ROMs, ↑BAP, GSH, CAT
Miscellaneous
Alcohol-induced hangover	Curcumin oral film	58	45 mg	One time	↓Dizziness, stomachache, palpitation	(722)
Episiotomy	Curcumin	117	–	–	↓REEDA score	(724)
Episiotomy healing process	Curcumin cream	120	2%	10 days	↓Pain, ↑wound healing	(725)
Hyperuricemia	Curcumin	39	500 mg/day	8 weeks	↓Serum urate	(727)
Age-related sarcopenia	Curcumin + WPI + ω-3 fatty acids + rutin	37	500 mg/day + 20 g + 1.5 g/day + 500 mg/day	12 weeks	↑Knee extension strength, gait speed	(728)
Muscle damage activity	Curcumina (Theracurmin)	14	300 mg/day	4 weeks	↑MVC torque recovery, ↓CK	(733)
DOMS	Curcumin	17	2.5 g × 2/day	2.5 days (pre-and post-exercise)	↓Pain, CK activity, ↑muscle performance, IL-6	(734)
Dyspepsia	Curcumin	132	4 × 500 mg/day	4 wks	↓SODA score, pain	(723)
Gulf War illness	Curcumin	39	1000–4000 mg/day	30 ± 3 days	↓Severity	(726)
Positive fecal occult blood	Curcuminoids	28	5 × 470 mg/day	14 days	Safe and tolerated	(259)
Preeclampsia	Curcumin	47	100 mg/day	–	No significant effect	(735)
Radio- and chemotherapy-induced side effects	Curcumin (Meriva)	158	500 mg × 3/day	4 months	Safe and tolerable, ↓burden of side effects	(732)
TURP, TURB, and BPH	Curcuminoids + resveratrol + NAC + zinc	80	190 mg + 20 mg + 100 mg + 6 mg	10–60 days	↓Postoperative and late complications, duration of irritation	(729)
Women with self-perceived hair thinning	Neutrafol	40	4 capsules	6 months	↑Number of terminal and vellus hairs, hair growth, quality, volume, thickness	(730)

^aSymbols and abbreviations: ↑, Increase/Upregulation; ↓, Decrease/Downregulation; NR, Not reported; Aa, Aggregatibacter actinomycetemcomitans; ACPA, Anti-citrullinated protein antibody; ACT, Asthma control test; ADPKD, Autosomal dominant polycystic kidney disease; ALDH, Aldehyde dehydrogenase; ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; AOPPs, Advanced oxidation protein products; AST, Aspartate aminotransferase; BALP, Bone-specific alkaline phosphatase; BANA, N-benzoyl-DL-arginine-2-naphthylamide; CDSS, Calgary depression scale for schizophrenia; BAX, Bcl-2 associated X-protein; BCL-2, B-cell lymphoma 2;BDNF, Brain-derived neurotrophic factor; BMD, Bone mineral density; BPH, Benign prostatic hyperplasia; BSE, Boswellia serra extract; BVAS, Birmingham vascular activity score; CA19-9, Carbohydrate 19-9; CAL, Clinical attachment level; CAT, Catalase; CD133, Cluster of differentiation; CDAI, Crohn’s disease activity index; CEA, Carcinoembryonic antigen; CFU, Colony forming unit; CGRP, Calcitonin gene related peptide; CK, Creatinine kinase; CKD, Chronic kidney disease; CK-MB, Creatinine kinase, MB fraction; CLDM, Curcumin liquid droplet micellar formulation; CLDQ, Chronic liver disease questionnaire; Coll2-1, serum type 2 collagen peptide; COX-2, Cyclooxygenase 2; CRP, C-reactive protein; CTx, C-terminal cross-linking telopeptide of type I collagen; CUA, Combined unique activity; Cur, Curcumin; CXCl1, CXC motif chemokine ligand 1; ESR, Erythrocyte sedimentation rate; DAS, Disease activity score; DASS-21, Depression, anxiety, stress scale-21; dFLC, Difference between clonal and non-clonal free-light chain; DFP, Deferiprone; DLQI, Dermatology life quality index; DMD, Duchenne muscular dystrophy, DNA, Deoxyribonucleic acid; DOMS, Delayed onset muscle soreness; EEG, Electroencephalogram; FEV, Forced expiratory volume; FF score, Fibromyalgia and fatigue rating score; FIHOA, Functional index for hand osteoarthritis; FLC, Free-light chain; FLIP, FLICE inhibitory proteins; FMD, Brachial artery flow-mediated dilation; FOXP3, Forkhead box P3; FSHD, Facioscapulohumeral dystrophy; FVC, Forced vital capacity; GI, Gingival index; GLA, Gamma linoleic acid; GPx, Glutathione peroxidase; GSH, Glutathione; GSK, Glycogen synthase kinase-3 beta; GSRS, Gastrointestinal symptom rating scale; H₂O, Water; H₂O₂, Hydrogen peroxide; HAM/TSP, HTLV-1-associated myelopathy/tropical spastic paraparesis; Hb, Hemoglobin; HDL, High-density lipoprotein; HDL-C, HDL-cholesterol; HDR, Headache daily results; HNC, Head and neck cancer; HOMA-β, Homeostatic model assessment for pancreatic beta cell function; HOMA-IR, Homeostatic model assessment for insulin resistance; HSC, Hematopoietic stem cell; hs-CRP, High-sensitivity C-reactive protein; HTLV-1, Human lymphotropic virus type-1; IAPP; Islet amyloid polypeptide; IBD, Inflammatory bowel disease; IBS, Inflammatory bowel syndrome; ICAM, Intracellular adhesion molecule; IFN, Interferon; iFLC, Involved free-light chain ratio; IFNγ, Interferon gamma; IIEF-5, 5-item version of the international index of erectile function; IL, Interleukin; IPSS, International prostate symptom score; IPSS-S, International prostate symptom score-storage sub score; IPSS-V, International prostate symptom score-voiding sub score; JKOM, Japanese knee osteoarthritis measure; JOA, Japanese orthopedic association, LDL, Low-density lipoprotein; LDL-C, LDL cholesterol; LDLR, LDL receptor; LDSI, liver disease symptom index; LGMD, Limb girdle muscular dystrophy; LNAA, Large neutral amino acids; LV, Left ventricular; MAFbx, Muscle atrophy F-box; MCP-1, Monocyte chemoattractant protein-1; MDA, Malondialdehyde; MDS-UPDRS, Movement Disorder Society sponsored revision of the Unified Parkinson’s Disease Rating Scale; MELD, Model for end-stage liver disease; MGI, Modified gingival index; MHb, Methemoglobin; MI, Myocardial infarction; MIF, Monocyte inhibitory factor; miRNA, Micro RNA; MMP, Matrix metalloproteinase; MN, Micronuclei; MPO, Myeloperoxidase; MSM, Methylsulfonyl methane; MVC, Maximal voluntary contraction; NAC: N-acetylcysteine; NAIOS, Nutraceuticals with anti-inflammatory, oxidative and nitrosative stress; NF-κB, Nuclear factor kappa B; NLC, Nanostructured lipid carriers; NMF, Natural moisturizing factor; NO, Nitric oxide; NO-adducts, Nitroso-adducts; NTBI, Non-transferrin-bound iron; NT-proBNP, N-terminal pro hormone B-type natriuretic peptide; OM, Oral mucositis; ORR, Objective response rate; OSDI, Ocular surface disease index; OSE, Oxidative-specific epitopes; PANSS, Positive and negative symptoms scale; PASI, Psoriasis area severity index; PBE, Pine bark extract; PBI, Papillary bleeding index; PCI, percutaneous coronary intervention; PCOS, Polycystic ovarian syndrome; PCr/Pi: Phosphocreatine-to-inorganic phosphate ratio; PCS, P-cresyl sulfate; PCT, Procalcitonin; PD, Pocket depth; PDT, Photodynamic therapy; PGC-1α, Peroxisome proliferator and activated γ receptor coactivator 1 alpha; PGE2, Prostaglandin E2; PI, Plaque index; PhK, Phosphorylase kinase; Pg, Porphyromonas gingivalis; PPBS, Postprandial blood glucose; PPD, Probing pocket depth; ppFEV₁, Predicted forced expiratory volume in one second; PPFT, Periprostatic fat thickness; PON1, paraoxonase-1; PSA, Prostate-specific antigen; PSQI, Pittsburgh sleep quality index; PTH, Parathyroid hormone; PV, Prostatic volume; Q_max, maximum flow rate; QoL, Quality of life; QUICKI, quantitative insulin sensitivity check index; RA, Rheumatoid arthritis; RAS, Recurrent aphthous stomatitis; REEDA, Redness, edema, ecchymosis, discharge, approximation; REU, Reticular erosive ulcerative score; RF, Rheumatoid factor; rFLC, Free-light chain ratio; RISR, Radiation-induced skin reactions; ROM, Range of motion; RORγt, Retinoic-acid-receptor-related orphan nuclear receptor gamma; RT, radiotherapy; SBI, Sulcus bleeding index; SBP, Systolic blood pressure; SCCAI, Simple clinical colitis activity index; SF-36, Short-form healthy survey; SJC, Swelling joint count; SMCs, Subjective memory complaints; SOD, Superoxide dismutase; SODA, Severity of dyspepsia assessment; SOFA, Sequential organ failure assessment; Sp, Substance P; SPEED, Standard patient evaluation of eye dryness; SRT, Selective reminding test; SSQOL, Stroke-specific quality of life; TAC, Total antioxidant capacity; TBARS, Thiobarbituric acid reactive substances; TBUT, tear-film break-up time; TC, Total cholesterol; TEWL, Transepidermal water loss; Tf, Tannerella forsythia; TG, Triglyceride; TGF-β, Transforming growth factor-beta; TIBC, Total iron binding capacity; TJC, Tender joint count; TLC, Total lymphocyte count; TLR4, Toll-like receptor 4; TN, Total nitrite; TNF-α, Tumor necrosis factor alpha; TRP, Tryptophan; TRR, Transferrin receptor; TURB, Transurethral resection of bladder; TURP, Transurethral resection of prostate; UGT, Uridine diphosphate glucuronosyltransferase; uDPYD, Urinary deoxypyridinoline; UIBC, Unsaturated iron-binding capacity; VAS, Visual analog scale; VCAM, Vascular cell adhesion molecule; VEGF, Vascular endothelial growth factor; VO₂ max, Maximal oxygen consumption; WBC, White blood cells; WOMAC, Western Ontario and McMaster Universities osteoarthritis index.

Figure 3.

Diverse function of turmeric and/or curcumin against diseases. This figure shows the diseases against which turmeric and/or curcumin are shown to be effective.

4.1. Methodology for Literature Search and Study Selection

4.1.1. Protocol

The systematic protocol was prepared, and a literature survey was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Figure 4).¹⁰¹

Figure 4.

Flowcharts of the result of literature survey for turmeric (left) and curcumin (right).

4.1.2. Search Strategy and Eligibility Criteria

A systematic literature search of PubMed and Scopus was performed in June 2022 to select relevant studies. The keywords were “curcumin and clinical trials” and “turmeric and clinical trials”. The search results were analyzed thoroughly for relevant keywords.

Inclusion criteria applied to the turmeric-based studies were: (a) healthy or diseased human subjects with analysis of the effects of pure turmeric powder, C. longa extract, formulation, and turmeric oil alone or in combination with other drugs/phytochemicals/extracts; (b) only studies of turmeric from C. longa; and (c) published in English. The exclusion criteria were: (a) preclinical studies of the effect of turmeric, such cell lines and animal models; (b) studies on curcumin, its formulations, and pure form of curcuminoids; (c) published in a language other than English; (d) review articles; (e) meta-analyses; (f) in silico studies; (g) editorials; (h) errata; (i) conference abstracts; (j) case reports; and (k) surveys.¹⁰¹

The inclusion criteria for curcumin-based studies were: (a) healthy or diseased human subjects with analysis of the effects of pure curcumin, pure curcumin in combination with other drugs/phytochemicals/extracts, curcumin formulations, and pure curcuminoids; and (b) published in English. The exclusion criteria were: (a) preclinical studies in cell lines and animal models; (b) studies on turmeric and its extract; (c) published in a language other than English; (d) review articles; (e) meta-analyses; (f) in silico studies; (g) editorials; (h) errata; (i) conference abstracts; (j) case reports; (k) surveys; (l) study protocols; and (m) observational studies.¹⁰¹

4.1.3. Study Selection

The articles were screened in two phases to filter out non-relevant studies. Mining was performed by thoroughly screening the title and abstract for keywords. Common articles appearing in both databases, such as errata and retracted manuscripts, systematic and narrative reviews, and in silico, in vitro, and in vivo studies, were excluded. In the second phase, we performed in-depth mining of the full texts and eliminated those that did not meet the eligibility criteria (Figure 4).¹⁰¹

The literature search in PubMed resulted in 262 documents for the search term “turmeric and clinical trials” after filtering for clinical trials only. Of these, 148 references did not meet the inclusion criteria and were eliminated. The remaining 114 clinical trials were included in the systematic review.

Scopus mining for the keywords “turmeric and clinical trials” yielded 346 documents. After excluding the reviews, errata, editorials, and book chapters, the remaining references were thoroughly examined for the inclusion and exclusion criteria. Of the original 346 documents, 242 were eliminated for failure to meet eligibility criteria. The remaining 104 were evaluated and included in the systematic review. After a thorough literature survey of both databases, 70 articles were found in both, 44 of which were unique to PubMed and 34 of which were unique to Scopus. Hence, a total of 148 were selected for the study after combining the search results and removing duplicates for the term “turmeric and clinical trials.”

Similarly, literature mining in PubMed yielded 458 documents for the keywords “curcumin and clinical trials” after selecting only clinical trials. The examination resulted in the elimination of 128 articles for failing to meet the inclusion criteria. The remaining 330 articles were considered in this review. The search of Scopus for “curcumin and clinical trials” yielded 1248 documents after filtering out the reviews, errata, editorials, book chapters, and articles in languages other than English. Of these, 878 did not meet eligibility criteria and were eliminated, leaving 370 articles that were evaluated in this review. We identified 260 papers in both databases: 70 were unique to PubMed and 110 were unique to Scopus. A total of 440 were selected for the study after combining the search results and removing duplicates.

4.1.4. Data Extraction

The clinical trials of curcumin as a pure compound and/or its derivatives and curcuminoids (pure compounds), turmeric and its formulations, type of study (clinical trials only), mechanism of action, effect or outcome, pharmacokinetics (if any), author, and year of publication were all examined.

4.2. Safety Profile of Turmeric/Curcumin

Accumulating evidence has suggested curcumin consumption is safe and well tolerated in humans with no or limited side effects (Tables 1 and 2).

Turmeric and its formulations were reported to improve various conditions in healthy individuals, reducing their risk of developing chronic diseases. A diverse range of studies have reported the tolerability of turmeric and its formulations in humans.^102−105 For instance, a single dose of a 10 g turmeric root extract formulation in aged individuals improved oxygenation and cerebral blood flow, which are associated with improving brain activity.¹⁰⁶ In another study, taking 1500 mg/day of BCM-95 (turmeric oil-based curcumin formulation) for 12 months stabilized cognitive function in older adults when compared to a placebo, recipients of which showed reduced cognitive function over the same period.¹⁰⁷ In another study, consumption of 1500 mg/day of C. longa extract for 30 days reduced inflammation and muscle damage in marathon runners by increasing levels of the anti-inflammatory cytokine IL-10 and reducing the secretion of myoglobin.¹⁰⁸ Another randomized trial demonstrated that curcuma extract restores ferritin levels and decreases hepcidin levels, which might help in combating iron deficiency and chronic inflammation in healthy individuals.¹⁰⁹ In premenopausal women, a botanical supplement containing turmeric, when taken for 12 weeks, decreased the levels of serum dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, and estrone-sulfate, thus improving hormone metabolism.¹¹⁰ Turmeric formulations relieve abdominal pain in inflammatory bowel disease (IBD) and musculoskeletal and joint pain, and improve the symptoms of discomfort.^111−113 One study suggested that consumption of curry containing 0.5 g turmeric remarkably increased breath hydrogen levels, suggesting activation of hydrogen-producing gut microbiota and improved bowel motility.¹¹⁴ Studies have also shown that turmeric elevates serum insulin levels and provides antioxidant activity in healthy subjects.^115,116 Moreover, C. longa inhibited the activities of cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6).¹¹⁷ It was also found to regulate the metabolism of bile acids when taken with medium- or high-fat meals.¹¹⁸ Turmeric enhances plasma levels of geranylgeronic, cinnamic, phenylacetic acids, and digoxin in healthy volunteers.^119−121 Administration of C. longa extract (500 mg/day) for 3 weeks produced a hemostatic effect in healthy adults (n = 25).¹²² In a study of healthy adults, supplementation with two capsules per day of Infla-kine (a formulation of a natural product with BCM-95 as its one ingredient) for 4 weeks remarkably reduced the expression of inflammatory markers IL-6, IL-8, TNF-α, and NF-κB in peripheral blood mononuclear cells (PBMCs).¹²³ Another randomized controlled trial suggested that turmeric tablets and extract had the potential to improve skin barrier function in 4 weeks by effectively reducing transepidermal water loss (TEWL) and increasing face water content .¹²⁴ Ahmed and colleagues demonstrated that ingested curcumin meal (400 mg) exhibits poor bioavailability in healthy people (n = 14) for both curcumin and curcuminoids compared to turmeric powder meal (400 mg curcumin).¹²⁵ A turmeric matrix formulation was shown to increase curcumin absorption in 15 healthy male volunteers.¹²⁶ A randomized, crossover clinical trial of a single oral dose of dried and liquid micellar formulations of turmeric (300 and 1000 mg, respectively) remarkably increased plasma curcuminoid levels compared to standard turmeric extract (1500 mg), phytosome turmeric formulation (1000 mg), and curcuminoid plus piperine (1515 mg).¹²⁷ Moreover, a curcumin formulation with volatile oils of turmeric increased the relative absorption of curcumin compared to a standard curcumin mixture and curcumin in combination with a hydrophilic carrier.¹²⁸ In another study, the turmeric formulations STE95 (95% turmeric extract) and WDTE60N (a water-dispersible turmeric extract formulation containing 60% curcuminoids) were administered orally to 14 healthy adults. Individuals who consumed one capsule of WDTE60N per day (150 mg curcuminoids) and three capsules of STE95 (500 mg curcuminoids each) had similar plasma levels of free curcumin, total curcuminoids, tetrahydrocurcumin, and dimethoxycurcumin.¹²⁹ Further, plasma drug concentrations (Cmax) of curcumin were higher for WDTE60N at a 10-fold lower dose than STE95, demonstrating that WDTE60N has better absorption capacity and was also found to be safe and well tolerated.^129,130 Furthermore, supplementation with fermented turmeric powder up to 3 g for 12 weeks was safe and well tolerated in healthy subjects.¹³¹ A novel turmeric formulation, PUREMERIC (1 g/day), was shown to be safe and well tolerated with no hepatotoxicity in healthy subjects.^129,132 Another study showed that Theracurmin (600 mg) in combination with Boswellin Super (250 mg), Oligopin (100 mg), and methylsulfonylmethane (1500 mg) in healthy subjects had similar pharmacokinetics properties as Theracurmin (600 mg) alone.¹³³ However, some studies have reported that ingestion of turmeric does not impart any remarkable effects on general health.^134−136 In one study, turmeric supplementation with caffeine had a negative effect on hemodynamic responses as indicated by increased blood pressure and was found to be ineffective in improving running time during exercise.¹³⁷ Another study indicated that turmeric consumption can increase the risk of kidney stone formation as it increases urine oxalate levels.¹³⁸

In 1998, a pharmacokinetics study by Shoba et al. reported the safety profile and high absorption and bioavailability of curcumin in combination with piperine in humans.¹³⁹ Lecithinized curcumin in combination with piperine, administered at a dose of 2000 mg to 11 healthy volunteers, was highly bioavailable and had a long retention time.¹⁴⁰ Another study explored the efficacy of γ-cyclodextrin formulated curcumin (CW8) in terms of bioavailability compared with standard curcumin extract, curcumin phytosome formulation (CSL), and curcumin-containing rhizome extracted essential oils. Here, the highest absorption capacity for total curcuminoids was observed in CW8 for over 12 h along with curcumin and demethoxycurcumin.¹⁴¹ In addition, a drinkable preparation of Theracurmin was compared to three other curcumin drinks to determine its absorption potential in 24 subjects. Theracurmin had an area under the curve concentration (AUC) up to 1.5- to 4-fold higher than the comparator drinks, and plasma concentrations of curcumin were also 1.8- to 3.8-fold higher, demonstrating the relatively high absorption efficiency of the drink.¹⁴² Another study showed that Theracurmin enhanced the absorption of curcumin compared to curcumin powder in healthy adults.¹⁴³ Several other studies involving the administration of curcumin and its formulations in healthy humans also showed high absorption and bioavailability.^{59,126,144−151} Moreover, curcumin supplementation in combination with ferrous sulfate was shown to enhance serum levels of iron, total iron binding capacity, and hemoglobin in healthy subjects.¹⁵² Furthermore, the administration of curcumin to healthy patients was found to be safe and well tolerated.^{45,128,153−155} The health-promoting effect of the curcumin formulation Longvida was evaluated in healthy middle-aged individuals. Subjects who received 80 mg of Longvida per day for 4 weeks showed increased free-radical scavenging activity and a reduction in triglycerides, salivary amylase, soluble intercellular adhesion molecule (ICAM), and alanine amino transferase (ALT), as well as plasma levels of catalase, myeloperoxidase (MPO), and nitric oxide (NO).¹⁵⁶ Administration of 5 g curcumin in 18 healthy smokers produced a cardioprotective effect and remarkably modulated flow-mediated dilation (FMD) in female subjects.¹⁵⁷

Curcuminoid metabolites were detected in urine, 4 h after the consumption of the C3 complex (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) in healthy individuals (n = 15) using genetic expression and measurement assays.¹⁵⁸

Curcumin is a substrate for uridine diphosphate glucuronosyltransferase (UGTs). In all, 42 healthy individuals received 2920 mg of curcumin daily for a month in a study that showed no difference in colon UGT expression.¹⁵⁹ Concomitant consumption of curcumin in healthy volunteers with talinolol (beta-1 adrenoceptor blocker) yielded increased plasma concentrations of talinolol but reduced bioavailability, perhaps because of the low concentration of curcumin in the lumen.^160,161 Moreover, administration of curcumin (500 mg–6 g/day) in healthy volunteers for 7 days induced antioxidant activity by modulating cholesterol and triglycerides.¹⁶² Consumption of 500 mg curcumin capsules (equivalent to 150 mg curcumin concentration) protected against oxidative stress in human volunteers.¹⁶³ The effect of curcumin on the oral bioavailability of sulfasalazine was investigated in eight healthy human subjects, who showed remarkably increased plasma concentrations of sulfasalazine and reduced expression of breast cancer resistance protein (BCRP).¹⁶⁴ Therefore, curcumin is a safe and effective agent with a wide range of biological properties. Though its bioavailability remains low, this limitation can be mitigated by different formulations or concomitant administration with agents like piperine. In a randomized double-blind study, intravenous administration of liposomal curcumin (10–40 mg/m²) was safe and well tolerated and yielded a dose-dependent increase in plasma curcumin and tetrahydrocurcuminoid levels.¹⁶⁵ In a three-way crossover double-blind study, Sunagawa et al. compared the bioavailability of three different formulations of curcumin, namely Theracurmin, BCM-95 (micronized curcumin with turmeric oil), and Meriva (phospholipidated curcumin), in healthy subjects. Theracurmin showed higher absorption efficiency than the comparators.¹⁴⁹ In a randomized crossover trial, micellar curcumin (57-fold) showed the highest plasma AUC versus time curve, followed by the curcumin-γ-cyclodextrin complex (30-fold) compared to native curcumin in 12 healthy volunteers.¹⁶⁶ Oral curcumin supplementation (180 mg/day) for 18 months improved cognitive functions, including visual memory, attention, and selective reminding test score, and reduced amygdala degeneration, as shown by positron emission tomography in healthy adults aged 51–80 years.¹⁶⁷ Supplementation with bioavailable curcumin (CorcuRougue) for 4 weeks reduced white blood cell (WBC) and neutrophil counts and decreased neutrophil/lymphocyte ratio in healthy adults ⩾60 years old (n = 39).¹⁶⁸ Supplementation with a highly bioavailable form of curcumin (Cureit 500 mg/day) for 3 months improved handgrip strength, weightlifting capacity, and walking distance and reduced the time to walk the same distance in elderly subjects >65 years.¹⁶⁹ Hence, novel curcumin formulations such as Theracurmin, BCM-95, LipiSperse, Meriva, CurcuRougue, etc. have remarkably improved the bioavailability of curcumin in healthy volunteers.^149,168,170

The application of a curcumin-loaded nanocarrier lipid cream for 4 weeks reduced hydration of the stratum corneum, and urea content and increased transepidermal water loss and deep penetration into the skin among healthy volunteers.¹⁷¹ Curcumin supplementation (500 mg/day) for 3 days was not effective in preventing exertional heat-induced stress and inflammatory responses, though it did reduce TLR4 content in PBMCs 1 h after exercise in healthy volunteers.¹⁷² A study conducted by Thota et al. showed that curcumin alone (180 mg) or curcumin plus fish oil capsules 4 days a week reduced postprandial glucose and insulin levels in healthy volunteers (n = 10).¹⁷³ A randomized, double-blind, placebo-controlled study showed that 500 mg Cavacurcumin (highly bioavailable curcumin powder) supplementation along with ω-3 fatty acids (675 mg), astaxanthin (3 mg), gamma-linoleic acid (9.5 mg), tocotrienols (12.5 mg), hydroxytyrosol (6.25 mg), vitamin D3 (1000 IU), and potassium (12.75 mg) reduced serum levels of IL-6 and hs-CRP and systolic blood pressure in healthy volunteers (n = 76).¹⁷⁴ In another double-blind, placebo-controlled clinical trial, Actbiome (a novel formulation of curcumin and asafetida) reduced IL-10 level, gastrointestinal symptom rating scale score, and stool frequency, and enhanced gut health by favoring healthy microbiota, as shown by increased fecal levels of the bifidobacteria lactobacilli.¹⁷⁵ Curcumin supplementation (180 mg/day) for 7 days prior to strenuous eccentric contractions suppressed exercise-induced inflammation and plasma IL-8 levels in healthy volunteers.¹⁷⁶ The same supplementation (180 mg/day) for 7 days after exercise reduced creatinine kinase activity and muscle soreness and increased the maximal voluntary contraction torque and range of motion in the elbow joints of healthy volunteers.¹⁷⁶ In a randomized, double-blind clinical trial, Cureit administration (500 mg; single dose) reduced delayed onset of muscle soreness (DOMS), serum creatinine kinase levels, and visual analog scale (VAS) score and increased maximum oxygen consumption (VO₂max) in healthy and moderately active subjects (n = 30).¹⁷⁷ In a randomized, double-blind, partial replication study, 400 mg/day lipidated curcumin (Longvida) for 12 weeks reduced fatigue score and improved blood glucose levels, working memory and mood in healthy older people between 50–80 years of age.¹⁷⁸ Administration of curcumin (2 g/day) and piperine (20 mg/day) after 45 min exercise on an eccentric treadmill resulted in reduced levels of ubiquitin, muscle trophy F box (MAFbx)/atrogin-1, and chymotrypsin-like protease and increased DOMS time in recreationally active males and females.¹⁷⁹ In another study, 500 mg of HydroCurc (curcumin with LipiSperse) and 500 mg of maltodextrin after exercise reduced capillary lactate dehydrogenase, overall muscle pain, and thigh circumference in young and healthy males with strength training experience.¹⁸⁰ In another randomized controlled trial, curcumin (190 mg/day) and fenugreek fiber (300 mg/day) for 28 days enhanced the neuromuscular fatigue threshold after exercise in untrained college-aged subjects (n = 47).¹⁸¹ A randomized, double-blind, placebo-controlled clinical trial demonstrated that curcumin (1000 mg/day) reduced audio-reaction time, choice-based visual reaction time, and improved memory in 18 volunteers aged 30–65 years.¹⁸² This study also showed that curcumin-galactomannan (1000 mg/day) supplementation resulted in a remarkable increase in α- and β-waves of the brain and decreased the α/β ratio, audio-reaction time, choice-based visual reaction time, and improved memory in these volunteers.¹⁸² In a study of the effect of environmental heat and antioxidant (curcumin) ingestion in firefighters (n = 10 male adults), heat plus curcumin supplementation (1500 mg/dose) prior to exercise increased the levels of glutathione (GSH) in these subjects. However, antioxidant supplementation is not necessary for well-trained firefighters to bear heat stress.¹⁸³ Oral administration of curcumin tablets containing 1.5 g curcumin/69 mg curcuminoids had no remarkable effect on exercise-induced oxidative stress among trained military personnel or firefighters. However, 150–300 min/week exercise does not induce oxidative stress in these populations; therefore, further studies on untrained individuals are needed to understand the role of curcumin in stress-induced oxidative stress.¹⁸⁴ A randomized, double-blind, placebo-controlled study showed that curcumin supplementation (30 mg/day) along with hot water extracts of C. longa increased water content in the skin of healthy individuals.¹⁸⁵ In a triple-blind, randomized, and placebo-controlled trial, curcumin (1000 mg/day) resulted in a remarkable reduction in the number of hot flashes in postmenopausal women (n = 89).¹⁸⁶ Oral administration of bioavailable curcumin (150 mg/day, divided into 6 capsules) along with moderate aerobic exercise increased carotid arterial compliance in postmenopausal women.¹⁸⁷ Supplementation with nanomicelle curcumin (80 mg) alone or in combination with Nigella sativa oil (1000 mg) for 2–6 months increased plasma levels of miRNA-21 in postmenopausal women with low bone mass density.¹⁸⁸ Recently, daily curcumin supplementation (1000 mg/day) for 8 weeks reduced serum levels of malondialdehyde (MDA) and high-sensitivity CRP (hs-CRP) and increased the total antioxidant capacity in 81 healthy postmenopausal women.¹⁸⁹ In fertile women with regular menstrual cycles, encapsulated curcumin reduced the endometrial expression of VEGF (p < 0.05) and enhanced COX-2 expression (p > 0.05) compared to the placebo group.¹⁹⁰ Kothapally et al. showed that a novel curcumin formulation (curcumin ultra+) possessed enhanced bioavailability and reduced safety issues at 250 and 500 mg doses (single) compared to 1000 mg turmeric extract in healthy volunteers under fasting conditions.¹⁹¹ Loriczova et al. demonstrated that iron (18 mg and 65 mg) supplementation along with curcumin (500 mg) reduces iron-induced systemic inflammation by reducing plasma levels of TNF-α and thiobarbituric acid-reactive substances in healthy individuals compared to those who received a placebo.¹⁹² Oral administration of 500 mg/day curcumin and 20 mg/day piperine for 7 days was shown to reduce acute exercise-induced inflammation by decreasing levels of IL-2, TNF-α, interferon (INF), IL-6, and IL-10 in healthy male runners.¹⁹³ In contrast, supplementation with 10 different dietary components, including curcumin (900 mg), resveratrol (100 mg), tea extract (800 mg), pomegranate extract (250 mg), quercetin (650 mg), acetyl-l-carnitine (500 mg), lipoic acid (600 mg), sesamin (1 g), cinnamon bark extract (1.7 g), and fish oil (1 g) daily for 6 months had no remarkable effect on metabolic and cardiovascular function in non-obese, relatively healthy individuals (n = 60).¹⁹⁴ Curcuminoid (4 g/day) administration in healthy volunteers for 30 days had no effect on uridine diphosphate glucuronosyltransferase expression.¹⁵⁹

4.2.1. Effects of Turmeric and Curcumin on Autoimmune Diseases

Autoimmune diseases occur when the immune response targets an individual’s own immune system, which can progress to organ failure.^195,196 Autoimmune diseases are one of the leading causes of death in young and middle-aged people and predominantly affect women.^196,197 There are >100 different autoimmune diseases, including Graves’ disease, multiple sclerosis, psoriasis, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, type I diabetes, and vitiligo, which affect approximately 5%–8% of the population worldwide.^195−197 Most immunosuppressants, like chemotherapeutics and anti-inflammatory drugs, are aimed at reducing symptoms rather than offering a cure, and the use of these drugs over time leads to cytotoxicity, immunosuppression, and attack by opportunistic microbes.^195,198 Bioactive compounds, including baicalin, chrysin, curcumin, genistein, hesperetin, kaempferol, quercetin, tangeretin, and taxifolin have demonstrated efficacy as immunomodulators and in treating autoimmune diseases.^199,200 Several clinical studies have shown that curcumin is remarkably beneficial in treating various autoimmune diseases. For instance, in a randomized, double-blind, placebo-controlled clinical trial, nanocurcumin supplementation of 80 mg/day reduced serum levels of IL-17, retinoid-related orphan receptor gamma (RORγt), miR-200, miR-141, and miR-155 in 24 patients with ankylosing spondylitis.²⁰¹ The efficacy of curcumin was also investigated in various studies of rheumatoid arthritis. For example, a study on two different doses (500 and 1000 mg/day) of Acumin, a novel form of bioavailable curcumin, in 36 patients with rheumatoid arthritis showed a reduction in joint inflammation, pain, swelling, and tenderness. The treatment was also marked as safe and well tolerated.²⁰² In another study, administration of a bioavailable formulation of curcumin, BCM-95, alone or in combination with diclofenac sodium at a dosage of 1 g/day for 8 weeks suppressed pain and disease conditions in 45 patients with rheumatoid arthritis.²⁰³ A clinical trial conducted by Hemmati et al. showed that curcumex (curcumin, ginger, and black pepper) decreased the tender joint count (TJC), swelling joint count (SJC), disease activity score (DAS), and erythrocyte sedimentation rate (ESR) in patients with rheumatoid arthritis (n = 60).²⁰⁴ Curcumin in essential oil (0.1% w/w) reduced ESR, rheumatoid factor, CRP, anti-citrullinated protein antibody, plaque index (PI) score, pocket depth, and clinical attachment level in patients with rheumatoid arthritis and chronic periodontitis.²⁰⁵ In a randomized, double-blind, placebo-controlled clinical trial, the administration of nanocurcumin (40 mg) capsules 3 times a day for 12 weeks reduced the disease activity score of 28 joints (DAS-28 score), TJC, and SJC in 65 patients with rheumatoid arthritis.²⁰⁶ In a pilot study of nanocurcumin (20 mg/L) delivery using iontophoresis to the arthritic site for 8 months, there was reduced inflammation and protein denaturation in patients with rheumatoid arthritis (n = 10).²⁰⁷ Oral supplementation with curcumin (3 g/day) and acitretin (0.4 mg/kg/day) reduced the psoriasis area severity index (PASI) in patients with psoriasis versus those treated with only acitretin (a second-generation retinoid used as standard therapy for severe psoriasis).²⁰⁸ Curcumin (2 g/day for 12 weeks) also reduced IL-22 in patients with psoriasis.²⁰⁹ In addition, turmeric tonic was well tolerated and effective in the treatment of scalp psoriasis, reducing psoriasis-associated erythema and PASI score, and improving patient QoL.²¹⁰ Moreover, the application of 1% alcoholic extract of curcumin for 4 weeks suppressed phosphorylase kinase activity, CD8⁺ T cell activity, transferrin receptor, and severity of parakeratosis in psoriasis.²¹¹ Other studies reported similar outcomes in the treatment of plaque psoriasis with curcuma extract tablets, showing improved PASI and body surface area affected scores, suggesting that turmeric can be considered a leading potential treatment for psoriasis.^212−214

4.2.2. Effects of Turmeric and Curcumin on Cancers

Cancer is one of the most prevalent chronic diseases and the second most common cause of disease-related mortality worldwide after cardiovascular diseases.^215−219 According to Global Cancer Statistics 2020, >19 million people suffer from cancer every year, and approximately 10 million succumb to it.^9,216−221 Cancer is mainly a lifestyle disorder with major risk factors, including an unhealthy diet, consumption of alcohol and tobacco, and exposure to ultraviolet light and infectious agents.^54,222−229

Accumulating evidence has demonstrated the anticancer potential of turmeric and its principal constituent, curcumin, against various types of cancers. For instance, patients (n = 20) consuming 1 tablespoon of turmeric as part of a personalized diet for 3 weeks showed improved antioxidant and anticoagulant activities.²³⁰ In another study, patients treated with high-dose vitamin C (25–100 g/day) along with oral nutrient supplementation including curcumin (1–3 g/day) had improved QoL and survival (breast cancer, n = 4; liver cancer, n = 1; lung cancer, n = 1; nasopharynx carcinoma, n = 2; ovarian cancer, n = 1).²³¹ Gbolahan et al. demonstrated that curcumin phosphatidylcholine (4 g) plus irinotecan (200 mg/m²) is well tolerated without any dose-limiting toxicities in patients with solid tumors. This study also showed no apparent increase in irinotecan-associated toxicities in patients receiving curcumin supplementation.²³² In another study, administration of 180 mg/day Meriva for 8 weeks remarkably reduced TNF-α, TGFβ, IL-6, IL-8, MCP-1, CGRP, and hs-CRP levels and improved QoL in patients with solid tumors.²³³ Administration of 100 mg/m² curcumin for 8 h followed by dose escalation to 300 mg/m² for the next 6 h weekly for 8 weeks reduced levels of tumor markers, such as carbohydrate antigen-19-9 (CA-19-9), carcinoembryonic antigen (CEA), and prostate-specific antigen (PSA), in patients with advanced metastatic tumors.²³⁴ This phase I study also reported that 300 mg/m² curcumin administration is safe and well tolerated; however, there was no reduction in tumor burden or disease progression in treated patients.²³⁴ Further, 180 mg of Meriva per day for 8 weeks was found to be safe and well tolerated. The treatment increased QoL in patients and decreased systemic inflammation by inhibiting cytokines, such as TNF-α, TGF-β, IL-6, IL-8, hs-CRP, calcitonin gene-related peptide (CGRP), MCP-1, and substance P.²³⁵ Bladder cancer is associated with considerable morbidity and mortality, with a high rate of recurrence, and a poor prognosis.^221,236,237 Conventional chemotherapeutic agents are often intolerable due to strong systemic toxicity.^238,239 Curcumin has been shown to be effective against bladder cancer. For example, in a pilot study, curcumin (50 mg) once per week for 4 weeks followed by once per month for 2 months decreased the core lower urinary tract symptom score in patients with cystic glandularis (metastatic proliferative disease of the bladder) who remained symptomatic after primary therapies.²⁴⁰ Moreover, in a randomized double-blind clinical trial, 180 mg/day of nanocurcumin supplementation for 4 weeks increased the clinical response in 26 patients with bladder cancer.²⁴¹

Brain tumors are a common solid tumor in children and are associated with high mortality.²⁴² Studies have shown the efficacy of curcumin in treating brain tumors. For example, the intratumoral concentrations and tolerability were measured in patients with glioblastoma who received 70 mg micellar curcuminoids (57.4 mg curcumin) three times per day for 4 days. The mean concentrations of curcumin in the tumor and serum were 56 pg/mg and 253 ng/mL, respectively. The micellar formulation of curcumin was detectable, and levels of inorganic phosphate were elevated while decreasing the mean ratio of phosphocreatine to inorganic phosphate.²⁴³

Despite advancements in treatment modalities, breast cancer remains a leading cause of death in women worldwide.²²¹ Turmeric and its formulations have been long known for their anti-breast-cancer potential. For instance, consumption of the turmeric-containing San Huang decoction (10 g/day) a day before surgery and 7 days after surgery relieved postsurgical symptoms in patients with breast cancer, including reduced exudate drainage and an attenuated wound inflammation score by regulating CRP, IL-2 receptor (IL-2R), -6, -8, and TNF-α.²⁴⁴ Avila-Galvez et al. demonstrated that dietary supplementation with polyphenols, including turmeric, resulted in the accumulation and detection of turmeric in breast tissue biopsies.²⁴⁵ However, another study showed that turmeric in combination with ginger (each 1 g/day twice daily for 14 days) was not well tolerated in patients with cancer.²⁴⁶ In a multicenter prospective, single-arm clinical trial, oral intake of PureVida capsules (each capsule containing 50 mg curcumin extract, 460 mg fish oil, and 125 mg Hytolive powder) three times a day for 30 days reduced CRP levels and pain score in postmenopausal patients with breast cancer (n = 45).²⁴⁷ Another study showed that curcumin injection (300 mg/week) along with paclitaxel (80 mg/m²) enhanced the objective response rate and physiological performance in recurrent metastatic breast cancer.²⁴⁸ Furthermore, in a multicenter, double-blind study, the application of curcumin gel markedly reduced skin reactions and pain in patients with breast cancer and radiation-associated dermatitis (n = 171).²⁴⁹ In addition, a dose-escalating study of curcumin in combination with docetaxel ranging from 500 to 8000 mg/day (each 500 mg capsule contains 450 mg of curcumin) showed prominent antitumor activity in 10 patients with breast cancer.²⁵⁰ The majority of patients undergoing radiation suffer from radiation-induced dermatitis. In a multisite, double-blind, and placebo-controlled clinical trial of 686 patients with breast cancer, it was shown that the administration of curcumin (2000 mg/day) throughout radiation therapy (RT) and 1 week post-RT reduced the severity of radiation-induced dermatitis, though the effect was not statistically significant.²⁵¹ In another study, daily consumption of 6 g curcumin during RT inhibited radiation-associated dermatitis and showed that fewer patients in the treatment group suffered from moist desquamation.²⁵²

Cervical cancer is one of the most frequently diagnosed malignancies and the fourth leading cause of death among women worldwide.²²¹ Even though different treatment modalities have been developed, many patients succumb to death. However, Hidayat et al. demonstrated that curcumin taken daily (80 mg/day) for 7 days and until before RT increased radiosensitization by reducing survivin levels in patients with advanced cervical carcinoma (n = 40).²⁵³

Chronic myelogenous leukemia (CML) is a rare hematopoietic neoplasm predominantly caused by the Philadelphia chromosome [reciprocal translocation t (9; 22) (q34; q11)] and breakpoint cluster region protein (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1) fusion gene.²⁵⁴ CML has historically been a terminal condition with few effective treatments, including arsenic substances, cytostatic drugs, and radiation therapy.²⁵⁴ When turmeric powder was used in combination with imatinib therapy in CML patients for 6 weeks, the levels of NO, a critical marker of CML, were remarkably reduced. This suggests that turmeric can be used as an adjuvant with imatinib therapy in CML.²⁵⁵

Colorectal cancer (CRC) ranks third in incidence and second in cancer-associated deaths, representing about 1.9 million newly diagnosed cases and 935,000 deaths in 2020.²²¹ In dose escalation clinical trials, curcuma extract was well tolerated and reduced prostaglandin E2 in patients with CRC.^256,257 Recent clinical studies have opened the possibility of using curcumin as a therapeutic agent against this deadly disease. For instance, Howells et al. showed that oral curcumin (2 g/day) with FOLFOX and bevacizumab increased overall and progression-free survival in 18 patients with CRC.²⁵⁸ Curcuminoids (C3 complex) were administered in patients with colorectal endoscopy or surgical resection to determine the safety and bioavailability of the treatment. The patients were treated with 2.35 g/day curcuminoids for 14 days. Results showed the supplement was safe, and the compound was detectable in urine, plasma, and colonic mucosa in the majority of the patients. Curcuminoids were detectable in the colonic mucosa up to 40 h after consumption.²⁵⁹ In addition, a dose escalation study of curcumin C3 capsules ranging from 450 to 3600 mg/day in 15 patients for 4 months showed reduced PGE₂ levels with high tolerability and no toxic events associated with treatment.²⁶⁰ Similar treatment in patients with colorectal cancer showed reduced levels of M(1)G DNA adducts, and the 3.6 g dose of curcumin yielded detectable levels of the compound in the colorectum.²⁶¹ Curcumin was also reported to induce p53 and Bax expression in patients with colorectal cancer, causing apoptosis and DNA fragmentation and suppressing TNF-α and Bcl-2. The treatment also improved patients’ general health at a dosage of 360 mg thrice daily.²⁶² The combination of curcumin, 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in colorectal liver metastases reduced stem cell markers, such as aldehyde dehydrogenase and CD133.²⁶³ In addition, curcumin alone or in combination was safe and well tolerated, suggesting the potential of curcumin as an adjunct to chemotherapy.²⁶³ Another study showed that administration of curcumin (480 mg thrice daily) in combination with quercetin for 6 months in patients with familial adenomatous polyposis (FAP) reduced the size and number of polyps and adenomas in the intestine and rectum with no toxicity detected.²⁶⁴ Oral administration of 450–3600 mg/day curcumin 1 week prior to surgery showed poor bioavailability and insufficient biological activity in patients with CRC and hepatic metastases.²⁶⁵

Gastric cancer is among the deadliest cancers, with an estimated incidence of >1 million and 7,69,000 deaths worldwide, ranking fifth for incidence and fourth for mortality.²²¹ In a randomized clinical trial, turmeric administration of 1000 mg/day for 5 days remarkably reduced human EGFR 2 (Her2) levels in gastric cancer.²⁶⁶ A study of the efficacy of C. longa-containing alpha ointment to treat hand and foot syndrome in patients receiving chemotherapy for gastrointestinal cancer found that the ointment slightly delayed the onset of the syndrome onset.²⁶⁷ However, further studies are needed to assess the potential use of turmeric and curcumin in these patients.

Glioblastoma accounts for 48% of all primary cancers of the central nervous system. Despite advancements in multimodal treatment modalities, glioblastoma remains a devastating disease with poor prognosis and rare long-term survival.^268,269 Studies have shown promising results with curcumin in treating glioblastoma. For example, in a phase I dose escalation study, after the administration of renin-angiotensin system blockers, i.e., curcumin, propranolol, aliskiren cilazapril, celecoxib, piperine, aspirin, and metformin (piperine was ingested to enhance the absorption of curcumin), an increase in median survival (not statistically significant) was observed in patients with advanced-stage relapsed glioblastoma with a Karnofsky performance score of at least 60 (n = 10).²⁷⁰ In another study, Esposito et al. demonstrated that dietary supplementation with 1200 mg/day curcumin reduced the number and volume of cutaneous neurofibromas in patients with neurofibromatosis I, which is an autosomal dominant disorder associated with a predisposition to tumor development, including glioma (n = 11).²⁷¹

Head and neck squamous cell carcinoma is the sixth most frequently occurring cancer and belongs to the challenge-to-treat category of malignancies.²⁷² Several studies have reported the anti-head and neck cancer properties of turmeric and curcumin in humans. For example, 4 weeks’ treatment of head and neck cancer (HNC) with BCM-95 (500 mg/day), a turmeric formulation, reduced the incidence and severity of radiation-induced mucositis.²⁷³ Another clinical trial showed that the application of turmeric gel made of 1 g turmeric powder daily for an average of 37 days remarkably decreased pain score and provided pain relief in patients with oral cancer.²⁷⁴ Further, topical the application of Vicco turmeric cream reduced the occurrence of radiation-induced dermatitis in HNC.²⁷⁵ Similar results were observed in another study where treatment with turmeric alone or in combination with black pepper and Nigella sativa improved mouth opening and burning sensation and regulated SOD levels in patients with oral submucous fibrosis.^276,277 TurmNova, a novel bioavailable form of turmeric, was also found to be safe in treating oral submucous fibrosis.²⁷⁸ A study investigating the effect of a bioenhanced formulation of turmeric on patients with HNC and radiation-induced oral mucositis showed a reduction in oral mucositis, oral pain, dysphagia, and dermatitis. Patients receiving the treatment also experienced less weight loss and better treatment compliance.^277,279 A similar study showed that gargling with turmeric mouthwash delayed the occurrence of radiation-induced oral mucositis in HNC.²⁸⁰ A combination of turmeric and honey remarkably improved oral mucositis assessment scores in patients undergoing chemotherapy.²⁸¹ Additionally, a microgranular formulation of curcumin (C3 complex) had better bioavailability and inhibited expression of fibroblast growth factor 2, granulocyte macrophage colony-stimulating unit, and IL-17 in head and neck cancer.²⁸² A randomized controlled trial showed that oral curcumin supplementation (300 mg, twice a day) for 6 months reduced burning sensation, increased mouth opening flexibility, tongue protrusion, and cheek flexibility in patients with oral submucous fibrosis (OSF).²⁸³ Treatment with a curcumin formulation (Longvida) also enhanced the mouth opening capacity in OSF (n = 30).²⁸⁴ Moreover, administration of curcumin (900 mg/day) plus piperine (5 mg/day) for 12 weeks reduced burning sensation and increased mouth opening flexibility in patients with OSF (n = 119). This study also showed that curcumin in combination with turmeric extract mouthwash had the same effect, also increasing the tongue protruding capacity in these patients.²⁷⁷ In another study, topical curcumin application alone or in combination with triamcinolone acetonide and hyaluronidase gel for 6 weeks reduced burning sensation, increased mouth opening flexibility, and improved the color of the mucosa in 120 patients with OSF.²⁸⁵ Sharma et al. showed that daily supplementation with 900 mg curcumin and 15 mg piperine for 12 weeks reduced the burning sensation and enhanced flexibility of the mouth opening in OSF (n = 41).²⁸⁶ The application of curcumin gel and curcumin buccal mucoadhesive patches for 4 weeks reduced burning sensation and lactate dehydrogenase (LDH) expression and increased mouth opening flexibility in patients with OSF.²⁸⁷ Also, administration of 500 mg/day curcumin for 3 months reduced burning sensation and increased mouth opening flexibility in OSF.²⁸⁸ In a double-blind randomized clinical trial, nanocurcumin (80 mg/day for 6 weeks) reduced radiation-induced mucositis in patients with HNC (n = 15) compared to placebo controls (n = 14).²⁸⁹ In another study, oral administration of 2000 mg/day curcumin for 4 weeks was associated with the complete remission (no symptoms) of oral lichen planus (OLP) lesions.²⁹⁰ Further, oral supplementation of 2000 mg/day curcumin for 7 days led to reduced lesion size, pain, and severity indices in patients with erosive OLP lesions (n = 20).²⁹¹ Next, a study conducted by Bakhshi et al. demonstrated that the application of nanocurcumin gel (1%) along with 0.1% triamcinolone resulted in a reduction in REU score and increased the efficacy score in patients with OLP (n = 31).²⁹² Pinheiro et al. showed that mouth rinsing with 20 mL curcumin (1.5 g/L) for 5 min followed by photo biomodulation (PBM-T) and photodynamic (PDT) therapies induced swift healing of mucositis.²⁹³ Neetha et al. showed that 950 mg/day curcumin alone reduced the expression of p53, Ki67, and cyclin D1 in patients with oral malignancies (n = 60). This study also showed that curcumin with green tea extract improved the clinical response rate.²⁹⁴ In a triple-blind, randomized pilot clinical trial mouth washing using 10 mL nanocurcumin (0.1%) three times a day (scored at 6th week) mitigated the risk of developing radiation-induced oral mucositis and delayed the onset and reduced the severity of symptoms in HNC.²⁹⁵ Nanomicelle curcumin (80 mg twice a day) reduced the pain score and severity of oral mucositis in patients undergoing chemotherapy with or without head and neck radiation therapy.²⁹⁶ In another study, nanocurcumin (80 mg/day for 4 weeks) reduced lesion size, pain, and burning sensation in patients with OLP (n = 57).²⁹⁷ The application of ora-base gel containing curcumin reduced the severity of oral mucositis during chemo-radiation in patients with HNC.²⁹⁸ These studies showed the remarkable potential of turmeric and curcumin in the prevention and treatment of oral diseases.

Hepatocellular carcinoma, or liver cancer, is the third most common cause of cancer-related mortality, with approximately 8,30,000 deaths in 2020.²²¹ Natural compounds have shown promising results in the treatment of liver cancer. In a randomized clinical trial, administration of curcuminoids (4 g/day) with piperine (40 mg/day) and taurine (500 mg/day) for 30 days reduced IL-10 and miR-21 expression in patients with hepatocellular cancer.²⁹⁹ However, more clinical studies are needed to establish curcumin and curcuminoids as potential therapeutics for liver cancer.

Multiple myeloma accounts for approximately 10% of all hematological malignancies.^300,301 There have been a few clinical studies of curcumin in multiple myeloma. For instance, curcumin decreased the free light-chain ratio (rFLC), urinary deoxypyridinoline (uDPYD), the difference between clonal and non-clonal light-chain (dFLC), involved free light-chain (iFLC), and creatinine levels in patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma.³⁰² Curcumin consumption was also shown to reduce paraprotein and urinary N-telopeptide of type I collagen levels in MGUS, suggesting the potential of curcumin in this cancer.³⁰³ Recently, a randomized, single-blind clinical trial conducted by Santosa et al. showed that curcumin administration (8 g/day) with melphalan (4 mg/m²) and prednisone (40 mg/m²) for 28 days reduced the levels of NF-κB, VEGF, TNF-α, and IL-6 in myeloma (n = 33).³⁰⁴

Pancreatic cancer is among the deadliest cancers in the world, with an incidence of 4,96,000 cases and 4,66,000 deaths in 2011.²²¹ Several studies have shown the therapeutic efficacy of curcumin in treating pancreatic cancer. A phase I clinical trial conducted by Kanai et al. showed that supplementation with escalating doses of bioavailable curcumin (Theracurmin, 47–1380 ng/mL) produced no adverse effects and was deemed safe in treating pancreatic (n = 14) or biliary duct cancer (n = 2).³⁰⁵ Another study showed that patients with advanced pancreatic cancer treated with 8 g/day curcumin (2 months) showed enhanced fat and muscle loss. This study also showed that the treatment shortened survival in patients with sarcopenia.³⁰⁶ Moreover, 8 g curcumin per day was found to be safe with no detectable toxicity. The treatment also modulated IL-6, IL-8, IL-10, IL-1RA, NF-κB, COX-2, and p-STAT-3.³⁰⁷ Curcumin (8 g/day) in combination with gemcitabine enhanced the chemotherapeutic effect in pancreatic cancer.³⁰⁸ Further, Pastorelli et al. showed that treatment with four 500 mg capsules per day increased the response rate, stable disease period, progression-free survival, and overall survival in pancreatic cancer (n = 44).³⁰⁹ In another study, curcumin intake of 8 g/day was shown to be safe, feasible, and no toxicity was reported in pancreatic cancer patients.³¹⁰

Prostate cancer is the second most common cancer by incidence and the fifth most common cause of death among men globally.²²¹ A plethora of studies have proven the ameliorating effect of turmeric and curcumin on prostate cancer. For instance, the turmeric formulation Zyflamed 780 mg/day was shown to reduce PSA, CRP, and NF-κB levels in 29 patients with prostate cancer.³¹¹ Additionally, turmeric formulations, such as combination phytotherapy (containing 400 mg/day turmeric), polyphenol (300 mg/day) tablets, and PROSTAFLOG (500 mg/day), were reported to inhibit the rise in PSA values in prostate cancer. Further, the treatment was reported to be well tolerated.^312−314 A pilot clinical trial showed that patients with prostate cancer who received 3 g/day curcumin from 1 week before radiotherapy until the completion of radiotherapy showed reduced urinary symptoms, including decreased urinate frequency, hurrying to get to the toilet, sleeplessness, unintentional release of urine, limitation of daily activity, and difficulty going out. The study also demonstrated the radioprotective effect of curcumin.³¹⁵ In another study, supplementation with 6000 mg/day of curcumin in prostate cancer was found to be safe and tolerable with no reported toxicity.³¹⁶ In a single center, randomized, and placebo-controlled clinical trial, Qiao et al. showed that curcumin (2.25 g/day) along with tamsulosin and finasteride for 6 months reduced waist circumference, periprostatic fat thickness, prostatic volume, international prostate symptom score (IPSS)-total, IPSS-storage subscore, and IPSS-voiding subscore and improved the maximum flow rate, 5-item version of the international index of erectile function, and QoL in patients with benign prostate hyperplasia (n = 60).³¹⁷ In a double-blind clinical trial of patients with prostate cancer undergoing radiotherapy (RT), a decreased susceptibility to proctitis was observed with nanocurcumin (120 mg/day) administered 3 days prior to and during RT compared to patients who received a placebo. Nevertheless, no remarkable difference was found in RT-induced cystitis, hematological imbalance, toxicities, or tumor growth response.³¹⁸ A randomized double-blind placebo-controlled study showed that curcumin (1440 mg/day) for 6 months reduced circulating levels of PSA among patients with prostate cancer and intermittent androgen deprivation (n = 49).³¹⁹ This study also showed no adverse side effects associated with curcumin.³¹⁹ A multicenter international randomized study showed that 200 mg/day curcumin along with chondroitin sulfate, hyaluronic acid, and quercetin, reduced urinary incontinence and improved QoL in patients with prostate cancer undergoing RT.³²⁰ In addition, Meriva, the lecithinized and bioavailable form of curcumin, administered at 200 mg/day of curcumin, with standard therapy for 24 weeks in prostatic hyperplasia, showed no adverse effects, improved QoL, reduced signs and symptoms of hyperplasia, and decreased infections and urinary block.³²¹ Another study explored the effect of curcumin on oxidative health in patients with prostate cancer undergoing RT. Patients given six capsules, each containing 373 mg curcumin, exhibited elevated total antioxidant activity (TAC) and decreased superoxide dismutase (SOD).³²² Moreover, treatment of patients with prostate cancer (n = 45) using curcumin 3 g/day (with turmeric oil 228 mg/day) 1 week prior to RT until completion effectively reduced the frequency of urination, sleeplessness, hurry to get to the toilet, limitation of daily activity, and unintentional release of urine.³¹⁵ In contrast, a multicenter randomized phase II clinical trial showed that curcumin 6 g/day for 7 consecutive days with docetaxel 75 mg/m² on day 1 of the cycle for 3 weeks for 6 cycles reduced progression-free survival and overall survival compared to docetaxel and placebo in castration-resistant prostate cancer, suggesting the curcumin plus docetaxel combination was not efficacious or recommended for these patients.³²³

Curcumin has also been shown to be effective against thyroid cancer, which ranks ninth in incidence.^221,324,325 In a double-blind, placebo-controlled clinical trial, nanocurcumin with radiolabeled iodine treatment was associated with a lower frequency of increased micronuclei in lymphocytes versus the placebo group in patients with differentiated thyroid carcinoma.³²⁵ The administration of curcumin, Boswellia, and spirulina extracts (50, 50, and 400 mg) twice a day for 12 weeks remarkably decreased the size of nodule areas in patients with benign thyroid nodules.³²⁶

Curcumin has also been shown to be effective in treating premalignant lesions. A study by Cheng et al. showed the efficacy of curcumin as a potential chemopreventive agent in patients with premalignant lesions. In this study, the dose escalation of curcumin (500–12000 mg/day) showed that dosages up to 8000 mg/day were not toxic in humans and could act as a potential chemopreventive agent by decreasing the lesions in premalignant patients.³²⁷

4.2.3. Effects of Turmeric and Curcumin on Cardiovascular Diseases

Cardiovascular diseases include a wide range of pathologies of the cardiac muscle and vascular system.³²⁸ It is the greatest cause of morbidity and mortality worldwide.^329,330 Studies have shown that maintaining healthy lifestyle modifications like regular exercise could be beneficial in reducing cardiovascular risk. The effect of curcumin on central arterial hemodynamics when used in combination with regular exercise was explored in postmenopausal women. Participants who received 150 mg curcumin per day along with excercise for 8 weeks showed a reduction in left ventricle afterload, aortic brachial systolic BP (SBP), and aortic augmentation index (Aix), suggesting a benefit associated with daily ingestion of curcumin capsules.³³¹ The efficacy of curcumin in combination with phytosterols was also determined in hypercholesterolemia, with subjects receiving 200 mg of curcumin per day for four weeks. The study showed that combination treatment was more effective in suppressing total cholesterol (TC) and low-density lipid cholesterol (LDL-c) in subjects versus phytosterols or curcumin monotherapies.³³² Acute coronary syndrome (ACS) is clinically consistent with acute myocardial ischemia and is usually accompanied by a decreased blood supply to the heart.³³³ A clinical study in 121 patients after coronary artery bypass grafting showed that curcuminoid capsules administered at a dose of 4 g/day provided a cardioprotective effect by suppressing surgery-associated myocardial infarction (MI), CRP, MDA, and N-terminal pro-B-type natriuretic peptide (NT-proBNP).³³⁴ A pilot randomized double-blind clinical trial showed that curcumin administration (2000 mg/day) reduced triglycerides, LDL cholesterol, and very low-density lipoprotein (VLDL) cholesterol in patients diagnosed with coronary artery disease (n = 33).³³⁵ Moreover, the effect of curcumin on the blood lipid profile was explored in 36 elderly subjects by administering 1 or 4 g of curcumin per day for 6 months. The treatment did not have a remarkable effect on lipid levels (triacylglycerols, or total, LDL, and high-density lipoprotein [HDL] cholesterol) throughout the study period, although plasma curcumin was positively correlated with serum cholesterol. The levels of ALT were also decreased after long-term treatment.³³⁶ In another study, the administration of a nanomicelle formulation of curcumin (80 mg/day) reduced expression of MMP-9 in PBMCs and activities of both MMP-9 and matrix metalloproteinase 2 (MMP-2) in patients with coronary artery disease (n = 70).³³⁷ Administration of curcumin 45 mg/day in patients with coronary heart disease every day for 7 days prior to percutaneous coronary intervention (PCI) and 2 days after PCI was shown to reduce serum levels of inflammatory markers, including hs-CRP and sCD40L.³³⁸ In addition, a randomized double-blind and placebo-controlled clinical trial showed that 300 mg/day of curcumin reduced ESR, TNF-α, CRP, and the Birmingham vascular activity score in 246 patients diagnosed with Takayasu arteritis, a condition of granulomatous chronic inflammation in the aorta and its main branches.³³⁹ Further, a randomized pilot clinical trial showed that oral administration of nanomicelle curcumin (480 mg) prior to PCI resulted in reduced creatine kinase-MB (CK-MB) (not statistically significant).³⁴⁰ Treatment with curcumin (500 mg/day) and nanomicelle curcumin (80 mg/day) for 8 weeks decreased TC, triglycerides (TG), LDL-C, MDA, hs-CRP, and TNF-α, levels and increased total antioxidant capacity (TAC), IL-1β, SOD, and glutathione peroxidase (GPx) levels in patients undergoing elective coronary angioplasty.³⁴¹ Another study determined the effect of three escalating dose of curcumin on lipid levels in patients with ACS. The patients received 45 mg, 90 mg, and 180 mg curcumin per day for 2 months and changes in TC, LDL-C, HDL-C, and triglycerides were observed. Daily 45 mg dosing produced a trending reduction in TC and LDL-C.³⁴² In a study of 45 patients with Fallot tetralogy (congenital heart malformity) undergoing corrective surgery, daily oral administration of curcumin (45 mg) for 14 days reduced the expression of c-JNK and caspase 3 in endocardial biopsy samples during ischemic phases compared to placebo.³⁴³ This study also showed that curcumin reduced body temperature and improved ventricular functions such as tricuspid annular plane systolic extrusion, mean ejection fraction, and fractional shortening after surgery.³⁴³ In another study, a combination of dietary supplements containing 900 mg curcumin were given to 54 non-obese patients daily for 6 months to determine its effect on cardiovascular and metabolic health. The treatment did not yield any beneficial effect on arterial stiffness or endothelial function in these patients.¹⁹⁴

While curcumin holds promise as a therapy in cardiovascular disease because it reduces inflammation and lipid dynamics, it is crucial that further randomized clinical studies provide more insights into its value as a prescribed medication.

4.2.4. Effects of Turmeric and Curcumin on Endothelial Function

Endothelial function is critical in regulating vascular movement and the release of clotting factors.³⁴⁴ Few studies have been conducted to investigate the potential of curcumin in preventing endothelial dysfunction. The curcumin formulation, Longvida, at 2000 mg daily for 12 weeks was safe, well tolerated, and improved arterial endothelial function by decreasing oxidative stress in healthy middle-aged subjects.³⁴⁵ Additionally, curcumin administered to 32 postmenopausal women improved endothelial function by reducing systolic blood pressure (SBP) and elevating FMD and peak oxygen consumption (VO₂ peak). The treatment was also found to be safe, with no adverse effects.³⁴⁶

4.2.5. Effects of Turmeric and Curcumin on Gynecological Conditions

A plethora of studies have shown that gynecological conditions such as endometriosis, chronic pelvic pain, fibroids, menorrhagia, and polycystic ovary syndrome (PCOS) affect QoL and are risk factors for devastating conditions such as cardiovascular diseases (CVDs), malignancies, metabolic disorders, and psychological disorders.^347−349 Long-term use of conventional medicines, including metformin, oral contraceptives, or other drugs or hormones that induce ovulation and clomiphene citrate, leads to side effects including abdominal pain, nausea, and vomiting.³⁵⁰ Recent studies have shown that lifestyle changes with a healthy diet and regular exercise provide innumerable benefits in the prevention and treatment of these diseases.³⁵⁰ Natural products including turmeric and curcumin are extremely beneficial in treating these diseases as they are easily accessible, multitargeted, and associated with few side effects.³⁵⁰ For example, in a phase I dose escalation study, intravaginal administration of curcumin (500, 1000, 1500, and 2000 mg/day) for 14 days was safe and well tolerated in patients with cervical dysplasia.³⁵¹ In another study, intake of 1500 mg/day curcumin for 3 months increased the activity/expression of GPx, SOD, PPARγ coactivator 1 alpha (PGC-1α) and sirtuin 1 (SIRT1) in PCOS.³⁵² Curcumin 500 mg/day also remarkably reduced body weight, BMI, fasting plasma glucose (FPG), insulin, insulin resistance, TC, and LDL-C and increased insulin sensitivity, HDL-C, PPARγ, and LDLR in 60 patients with PCOS.³⁵³ Another randomized placebo-controlled trial showed that 8 weeks of curcumin therapy (93.34 mg twice daily) reduced body weight, body fat mass, waist circumference, fasting blood glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), TC, TG, and CRP in patients with PCOS.³⁵⁴ Patients with PCOS who received 1500 mg/day curcumin for 12 weeks experienced a remarkable reduction in FPG and dehydroepiandrosterone.³⁵⁵

Premenstrual syndrome (PMS) may be defined as a disorder associated with psychological and physical symptoms that occurs during the luteal phase of the menstrual cycle.³⁵⁶ A study was conducted to demonstrate the effect of turmeric alone and in combination with mefenamic acid in patients suffering from primary dysmenorrhea (PDM). It was concluded that the combination treatment effectively relieved the menstrual pain associated with PDM when taken for 5 days.³⁵⁷ Curcumin has also shown potential in mitigating the severity of postmenopausal symptoms. For example, curcumin ameliorated PMS symptoms in terms of mood, behavior, and physical symptoms by modulating neurotransmitters and inducing an anti-inflammatory effect in patients taking 100 mg curcumin every 12 h for 7 days prior to the menstrual cycle and for 3 days into the cycle. The treatment was evaluated for three consecutive cycles.³⁵⁸ The same dosage of curcumin was found to reduce the severity, physical symptoms, and mood swings associated with PMD. These changes might be due to the upregulation of brain-derived neurotrophic factor (BDNF) levels.³⁵⁹ A randomized, triple-blind and placebo-controlled (lactose powder) clinical trial showed that supplementation with curcumin (500 mg/day) and piperine (5 mg/day) for 10 days (7 days prior and 3 during the menstrual cycle) of each of 3 cycles remarkably reduced premenstrual syndrome screening tool score and dysmenorrhea-associated pain.³⁶⁰ In another study, Arabnezhad et al. showed that 500 mg of curcumin along with 5 mg piperine 7 days prior to and 3 days after menstruation remarkably increased vitamin D levels and reduced serum levels of aspartate amino transferase (AST) and bilirubin in women with PMS and dysmenorrhea (n = 36) compared to the placebo group (n = 37).³⁶¹ Further, administration of Ialuril soft gel tablets containing curcumin, quercetin, hyaluronic acid and chondroitin sulfate (2 pills/day for 12 weeks) reduced symptoms of dysmenorrhea, chronic pelvic pain, and dysuria in patients with endometriosis (n = 20).³⁶² Furthermore, administration of 1 g/day of curcuminoids reduced VAS score and pain in patients after laparoscopic hysterectomy.^363,364

4.2.6. Turmeric and Curcumin for Infectious Diseases

The diseases caused by microbial infections are fatal if not quickly diagnosed and treated and account for >25% of total annual deaths worldwide.³⁶⁵ Epidemics of both new- and old-world infectious diseases emerge on a regular basis, dramatically increasing the global infection burden against a background of persistently known infections.³⁶⁵ Recently, the outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a pandemic disease, coronavirus disease-19 (COVID-19), which resulted in devastating morbidity, mortality, and socioeconomic burdens.³⁶⁶ The common clinical symptoms of this disease include sore throat, cough, fatigue, fever, headache, breathlessness, and myalgia.³⁶⁷ Pneumonia, cytokine storm, acute respiratory distress syndrome, respiratory failure, and death are the symptoms of disease progression.³⁶⁷ Accumulating evidence suggests that increased consumption of phytochemicals or phytochemical-enriched foods, such as cereals, fruits, legumes, and vegetables, containing high amounts of carotenoids, flavonoids, isoflavones, isothiocyanates, phytosterols, and terpenoids reduces the prevalence and severity of COVID-19 disease.³⁶⁶ Naturally occurring spices such as turmeric and its component curcumin have also been shown to aid in disease prevention, reducing symptoms and disease burden in patients with COVID-19. For example, an ayurvedic formulation containing C. longa, known as AyurCov, was found to relieve the symptoms associated with COVID-19 infections. Increased real-time reverse transcription polymerase chain reaction (rRT-PCR) cycle threshold (Ct) values and an improved functional status were also reported in patients consuming supplement.³⁶⁸ Valizadeh et al. demonstrated that administration of 160 mg/day of nanocurcumin reduced mRNA and serum levels of IL-6 and IL-1β in 40 COVID-19 patients compared to placebo.³⁶⁹ In a triple-blind, randomized, and placebo-controlled clinical trial, nanocurcumin (40 mg, four capsules a day) for 2 weeks reduced the time taken to resolve the sore throat and serum CRP levels compared to placebo in 60 patients with COVID-19.³⁷⁰ An open-label randomized clinical trial showed that oral administration of nanocurcumin (40 mg, four capsules a day) for two weeks reduced symptoms including chills, cough, fever, myalgia, and tachypnea and increased oxygen saturation levels in patients with COVID-19 (n = 41).³⁷¹ In another triple-blind, randomized trial, administration of nanocurcumin (40 mg/capsule) four times a day reduced IFN gamma (IFN-γ) and T-box transcription factor 21 (TBX21) transcript expression and induced expression of TGF-β, IL-4, and forkhead box P3 (FOXP3) versus placebo, indicating that the nanocurcumin is effective against acute inflammatory responses.³⁷² Moreover, oral administration of 525 mg/day curcumin along with 2.5 mg/day piperine (twice daily) reduced symptom severity, red flag signs, and deterioration and increased oxygen saturation levels in patients who tested positive for COVID-19.³⁷³ In another study, Tahmasebi et al. showed that patients with COVID-19 (n = 80) treated with nanocurcumin 80 mg/day twice for 21 days had increased Treg cells and expression of FOXP3, IL-10, IL-35, and TGF-β compared to those who received a placebo.³⁷⁴ The same group later showed reduced circulating Th17 cells, RORγt, IL-17, IL-21, IL-23, and granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with COVID-19 treated with nanocurcumin 80 mg/day twice for 21 days compared to the placebo.³⁷⁵ These parameters were associated with nanocurcumin in both mild and severe COVID-19 after intervention compared to before intervention levels.³⁷⁵ This study also showed that nanocurcumin remarkably reduced COVID-19 symptoms such as fever, cough, and dyspnea, leading to reduced hospitalized duration and mortality.³⁷⁵ A randomized, double-blind, placebo-controlled study revealed that nanocurcumin supplementation (160 mg/day for 6 days) reduced symptom severity and duration of hospitalization and enhanced oxygen saturation levels in COVID-19.³⁷⁶ In addition, a placebo-controlled randomized trial of 240 mg/day nanocurcumin showed remarkably reduced mRNA expression of IFN-γ and TNF-α and serum levels of IFN-γ, IL-1β, and IL-6 in patients hospitalized with mild-to-moderate COVID-19. This study also showed that nanocurcumin reduced the mortality rate in these patients.³⁷⁷ Further, oral administration of 500 mg/day Azithromycin, 150 mg/day oseltamivir, 400 mg/day hydroxychloroquine for 5 days, and 3 g/day curcumin with 30 mL virgin coconut oil for 21 days reduced inflammatory cytokine levels including IL-1β, IL-2, IL-6, TNF-α, and IFN-β in patients with COVID-19.³⁷⁸ Furthermore, the ArtemiC oral spray (artemisinin 6 mg/mL, curcumin 20 mg/mL, frankincense 15 mg/mL, and vitamin C 60 mg/mL) given twice a day on day 1 and 2 of a double-blind multicenter phase II clinical trial showed remarkable clinical improvement, including reduced O₂ supplementation duration, fever duration, hospital admission time, and abnormal oxygen saturation (SpO₂) duration in patients with COVID-19 (n = 33), compared to those who received a placebo (n = 17).³⁷⁹ In another study, curcumin (1000 mg/day) and piperine (10 mg/day) combination treatment improved health status including ague, dry and sputum cough, dyspnea, headache, muscular pain, and sore throat at week 2 in 23 patients with COVID-19. This study also showed that curcumin in combination therapy remarkably improved weakness compared to the placebo (n = 24).³⁸⁰ Therefore, turmeric and curcumin have remarkable potential in the prevention and treatment of COVID-19.

Human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) continue to be a devastating global tragedy despite intense efforts to raise awareness.³⁸¹ Although antiretroviral therapies have reduced disease-associated deaths, the constant search for effective and curative treatment remains uncertain.³⁸¹ Phytochemicals, including curcumin, have been shown to reduce the severity of symptoms in patients with HIV and AIDS. For example, Silva et al. showed that 1000 mg/day curcumin for 30 days increased triglyceride levels but failed to alter energy substrate oxidation—neither at rest nor during physical activity—in patients with HIV/AIDS undergoing antiretroviral therapy (n = 20).³⁸² A pilot study showed that nanocurcumin (160 mg/day) for 10 days remarkably reduced levels of procalcitonin and TNF-α and lowered sequential organ failure assessment scores in critically ill patients with sepsis (n = 40).³⁸³ In another study, treatment with 0.75 mg/mL curcumin in combination with photodynamic therapy (20.1 J/cm²) led to a reduction in Streptococcus and Staphylococcus colony counts.³⁸⁴ Moreover, a vaginal polyherbal cream (containing curcumin extract) and curcumin vaginal capsule produced a high human papillomavirus (HPV) clearance rate in patients with HPV.³⁸⁵ However, another study showed that 1 g/day curcumin for 30 days had no remarkable effect in patients with HIV.³⁸⁶ Therefore, further studies are needed to understand the beneficial effect of curcumin in treating viral infections.

Turmeric and curcumin, alone or in combination with other compounds, have been proven effective in treating other infectious diseases. Oral administration of curcumin with hyaluronic acid (HA), chondroitin sulfate, and quercetin for 12 months reduced the frequency of urinary tract infections in postmenopausal women. The supplements were deemed safe, with no reported adverse events.³⁸⁷ In another study, Labban et al. showed that mouth rinsing with 100,000 UI/mL curcumin for 60 s followed by photodynamic therapy reduced the overall colony formation unit (CFU)/mL score and the occurrence of Candida albicans, C. tropicalis, and C. glabrata in habitual smokers with denture stomatitis (n = 45).³⁸⁸ A single-center, parallel-arm, and placebo-controlled trial showed that mouthwash using a 10 mL curcuminoid-chitosan formulation (100 mL containing 0.1 g commercial curcuminoid powder + 40 mL polyethylene glycol + 25 mL 2% chitosan + 15 mL sorbitol + 1 mL paraben + 100 μL NaOH) for 2 weeks produced a complete response in 80% of patients with denture stomatitis with enhanced anticandida activity, whereas only 30% of the patients showed a complete response when treated with chitosan alone.³⁸⁹ In another study, Naeini et al. showed that 10 days’ administration of nanocurcumin to patients in the intensive care unit (ICU) with sepsis remarkably reduced ESR, IL-8, neutrophils, platelets, presepsin, and WBCs and enhanced the lymphocyte count.³⁹⁰ Interestingly, nasogastric supplementation with nanocurcumin (160 mg/day for 14 days) in critically ill patients with sepsis in the ICU (n = 20) remarkably reduced the sequential organ failure assessment score (SOFA) and the duration of mechanical ventilation compared to the placebo (n = 20).³⁹¹ This study also showed that serum levels of ICAM-1, IL-1β, IL-6, IL-18, MDA, vascular cell adhesion molecule 1 (VCAM-1), and transcript levels of Bcl-2 associated X (Bax) and TLR-4 were reduced, and levels of catalase, IL-10, SOD, TAC, Bcl-2, and Nrf-2 were increased in patients treated with nanocurcumin versus the placebo.³⁹¹ Moreover, serum fasting blood sugar (FBS), TG, TC, alkaline phosphatase (ALP), ALT, aspartate AST, gamma-glutamyl transferase (GGT), bilirubin, prealbumin, and creatinine levels were reduced after nanocurcumin treatment compared to baseline levels.³⁹¹ This study indicated that nanocurcumin might be a promising therapeutic tool in sepsis.

Studies have also investigated the effect of turmeric tablets in treating Helicobacter pylori infection, but they found that the treatment imparted no remarkable effects.³⁹² Turmeric-based antimicrobial soap remarkably reduced erythema, scaling, and desquamation in patients infected with Tinea corporis.³⁹³ A study conducted on 25 patients with H. pylori who received curcumin 30 mg twice daily showed a reduction in symptom severity and serum pepsinogens (sPGI and sPGII) after 2 months. It was also shown to improve dyspeptic symptoms and reduce gastric inflammation in these patients.³⁹⁴ Administration of 500–1500 mg/day curcumin with piperine for 4 weeks in patients infected with H. pyroli was found to be safe and suppressed dyspepsia symptoms.^395,396

4.2.7. Turmeric and curcumin in Inflammatory Disorders

Accumulating evidence over >200 years has established turmeric and curcuminoids as strong anti-inflammatory and antioxidant molecules useful in various disorders. Numerous clinical trials have explored their efficacy in the treatment and clinical management of inflammatory diseases. The first clinical trial for inflammatory diseases was carried out in 1937 by Oppenheimer to assess the effect of curcumin extracts on biliary disorders. Curcumin treatment caused rapid gall bladder clearance and provided benefits in chronic cholecystitis. Notably, one patient experienced a complete cure of the disease with no relapse.³⁹⁷ Since then, turmeric and its constituents, like curcumin, have been used in various formulations for the treatment of a variety of inflammatory ailments. For instance, patients with asthma can take C. longa capsules to delay the onset of asthmatic symptoms and reduce the need for short-acting β-adrenergic agonists (SaβAA) for acute attacks.³⁹⁸ In another study, turmeric (500 mg/day) reduced hs-CRP, IL-6, and TNF-α levels and increased albumin levels in patients undergoing chronic hemodialysis.³⁹⁹ Turmeric was also found to relieve joint pain in osteoarthritis. Multiple studies have shown that turmeric extract formulations such as B-Turmactive, TamaFlex, and Instaflex relieve joint pain and improve knee function and mobility. The formulations are safe and improve Western Ontario and McMaster Universities osteoarthritis index (WOMAC) scores as well as walking time and distance.^400−404 Treatment with turmeric extract alone and as formulations or combinations such as C. longa capsules, BCM-95, LI73014F2, and AINAT decreased WOMAC and VAS scores in arthritic patients and improved the levels of critical disease regulators including resistin, adiponectin, leptin, CRP, TNA-α, TNF receptor type II (TNFR2), IL-1β, reactive oxygen species (ROS), and MDA.^405−411 Other studies have reported that turmeric extract alone and in combination with Boswellia reduced levels of PGE 2 and improved walking distance, joint tenderness, pain scores, and range of motion (ROM) in patients.^412−416 An herbal-mineral formulation containing turmeric was also found to relieve pain and reduce disability score in arthritic adults.⁴¹⁷ Furthermore, treatment of osteoarthritis with bio-optimized C. longa capsules reduced patient global assessment of disease activity and serum type 2 collagen peptide (sColl2-1) and improved knee injury and osteoarthritis outcome and VAS scores.⁴¹⁸

Recently, Maulina et al. showed that 200 mg of curcumin thrice a day for 7 days prior to the protocol drastically reduced acute inflammation-associated pain compared to patients who received 500 mg of mefenamic acid (a standard non-steroidal anti-inflammatory drug) in patients undergoing surgical removal of an impacted third molar.⁴¹⁹ Oral administration of 80 mg/kg nanocurcumin daily for 4 months reduced levels of miR-17, miR-27, and IL-6 and increased expression of miR-146a, FOXP3, IL-10, and TGF-β compared to placebo controls in patients with ankylosing spondylitis.⁴²⁰ This study also showed that nanocurcumin supplementation effectively increased the population of regulatory T cells in these patients, indicating the effectiveness of curcumin in treating autoimmune diseases.⁴²⁰ Nanocurcumin supplementation of 80 mg/day for 8 weeks effectively increased Treg cell frequency and expression of FOXP3, TGF-β, IL-10, miRNA-25, and miRNA-106b in patients with Behcet’s disease (inflammatory disorder characterized by genital and oral ulcers, skin lesions, and gastrointestinal, articular, neurologic, ocular, and vascular involvement).⁴²¹ Moreover, 1000 mg/day of curcumin along with standard therapy for 30 days produced a remarkable reduction in ESR, eosinophils, and adverse events and improved weight and forced expiratory volume in 60 patients with bronchial asthma.⁴²² Another study showed that curcumin 1500 mg/day along with piperine 5 mg/day for 30 days remarkably decreased expression of IL-6 and increased forced expiratory volume in one second (FEV1), forced vital capacity, and asthma control test score in bronchial asthma (n = 40).⁴²³ In addition, the consumption of curcumin 375 mg thrice daily for 12 weeks was shown to improve chronic anterior uveitis.⁴²⁴ In another study, a turmeric formulation prepared as an eye drop was effective against eye infections and inflammation in addition to being safe and well tolerated in patients with ophthalmic diseases.⁴²⁵ In a randomized single-center clinical trial, curcumin (200 mg) with lutein (20 mg), zeaxanthin (4 mg), and vitamin D (600 IU) for 8 weeks reduced the Ocular Surface Disease Index score, the corneal and conjunctival staining score, the tear osmolarity, and MMP-9 positivity, and increased Schirmer’s strip wetness length, tear volume, the tear film break-up time score, and the Standard Patient Evaluation of Eye Dryness in patients with dry eye syndrome.⁴²⁶ A randomized clinical trial showed that curcumin 1 g/day for 3 months reduced ALP, bilirubin, the model for end-stage liver disease scores, and Child–Pugh scores in 60 patients with liver cirrhosis.⁴²⁷ Another study showed that curcumin (1 g/day) for 12 weeks remarkably increased CLDQ domain and SF-36 domain scores and reduced liver disease symptom index 2.0 domain score, indicating an improvement in disease state (n = 58).⁴²⁸ Topical application of curcumin (200 mg/pump) every 8 h for 3 days reduced mastitis and lowered erythema, pain, and tension scores in breastfeeding women with lactational mastitis (n = 63).⁴²⁹

The gall bladder stores the bile that is synthesized in the liver. Abnormal gall bladder function might be associated with diseases like pancreatitis and abnormal activities between the gall bladder and small intestines might cause small bowel obstruction.⁴³⁰ The effect of curcumin on modulating gallbladder function has been evaluated. For example, the effect of a 20 mg single dose of curcumin was examined in 12 healthy patients at different time intervals after dosing, ranging from 0.5 to 2 h. That single dose was sufficient to induce gall bladder contraction of approximately 9% at 2 h and decrease gall bladder volume.⁴³¹ Moreover, supplementation with curcumin (80 mg) enhanced gall bladder emptying by 23% in healthy subjects.⁴³² Another extended study by the same group demonstrated contraction of the gall bladder up to 50% at a 40 mg dose; however, an 80 mg dose was not associated with gall bladder contraction.⁴³³

C. longa was reported to have potential effects in the treatment of various gastrointestinal disorders. For example, a study reported the efficacy of turmeric in regulating gut dysbiosis in chronic kidney disease (CKD). Turmeric-based juice decreased plasma levels of p-cresyl sulfate (pCS), which is an important factor in the proper functioning of gut microbiota.⁴³⁴ Another study on postprandial distress syndrome associated with dyspepsia reported that treatment with C. longa capsules delayed the occurrence of functional dyspepsia, but also yielded a high recurrence rate.⁴³⁵ Other studies have evaluated the potential of turmeric in treating abdominal bloating associated with small bowel dysbiosis and irritable bowel syndrome. These studies found that turmeric tablets were effective in relieving abdominal pain and discomfort.^111,436C. longa capsules also displayed potential anti-ulcer activity by reducing peptic ulcers and relieving abdominal pain and discomfort.⁴³⁷ Supplementation with 500 mg of curcumin daily for 3 days in eight patients suffering from gastrointestinal damage suppressed inflammation and improved gastrointestinal function by suppressing intestinal fatty-acid-binding protein (I-FABP) and pro-inflammatory cytokines such as IL-1R, TNF-α, IL-10.⁴³⁸ However, an ayurvedic herbal formulation containing turmeric was not effective in improving gingival index (GI) symptoms in patients with inflammatory bowel syndrome.⁴³⁹ In another study, the effect of pure curcumin was assessed in five patients with ulcerative proctitis and five with Crohn’s disease. The patients received 550 mg of curcumin twice daily for the first month, followed by three doses of 550 mg of curcumin for another month. The patients with ulcerative proctitis experienced a decrease in abdominal pain, cramping, and muscle soreness, while those with Crohn’s disease experienced a reduction in Crohn’s Disease Activity Index scores and sedimentation rates.⁴⁴⁰ Patients with ulcerative colitis (UC) who consumed 2 g of curcumin (1 g each after breakfast and the evening meal) plus sulfasalazine (SZ) or mesalamine daily experienced a decrease in disease morbidity, and the treatment was found to be safe.⁴⁴¹ Similarly, a study by Lang et al. showed that taking curcumin with mesalamine (3 g) for a month was safe with no reported adverse effects in UC. The combined therapy was also shown to improve clinical presentation.⁴⁴² In another study involving 11 patients suffering from Crohn’s disease or UC, the effect of curcumin was investigated for its potential as an adjunct to conventional therapies. The patients received 1 g curcumin for the first 3 weeks followed 2 g from week 3 through 6, the 4 g curcumin from week 6 through 9. The doses were well tolerated and produced improvements in disease conditions.⁴⁴³ Moreover, treatment of Crohn’s disease (n = 40) with bioavailable curcumin (360 mg/day) for 12 weeks enhanced the clinical remission rate and anal lesion healing and reduced disease severity.⁴⁴⁴ Curcumin at 3 g/day for 6 months produced a remarkable reduction in Crohn’s disease recurrence rate.⁴⁴⁵ Another study of 48 patients with Crohn’s disease using curcumin (3 g/day) along with azathioprine (2.5 mg/kg/day) for 3 months showed a remarkable reduction in fecal calprotectin.⁴⁴⁶ Interestingly, another study revealed that nutraceutical therapy containing curcumin, Boswellia extract, fish peptides, bovine colostrum, and a multivitamin resulted in prolonged remission and weight restoration in patients with Crohn’s disease.⁴⁴⁷ A standardized preparation of curcumin, NCB-02, provided at 140 mg daily in combination with oral 5-aminosalicylates for 8 weeks was also shown to induce better clinical response and outcomes with no adverse side effects in patients with UC.⁴⁴⁸ Recently, Massodi et al. demonstrated that curcuminoids at 240 mg/day for 4 weeks in UC (n = 28) reduced the score for urgent defecation and the simple clinical colitis activity index along with improved self-reported well-being compared to placebo controls (n = 28).⁴⁴⁹ Curcumin (1000 mg/day) along with green tea (500 mg/day) and selenium (200 μg/day) increased disease improvement and remission rate in patients with UC.⁴⁵⁰ Administration of curcumin 1.5 g/day for 8 weeks remarkably decreased ESR, hs-CRP, and QoL in 70 patients with UC.⁴⁵¹ Further, supplementation with bioenhanced curcumin (2 mg/day for 6 weeks) increased the remission rate, clinical response rate, and sustained remission period in UC.⁴⁵² Furthermore, curcumin in combination with fennel essential oil (CU-FEO) administered at a dose of 84 mg per day in 116 patients for 30 days was found to be safe, well tolerated, and effective in reducing abdominal pain and other symptoms associated with severe IBD.⁴⁵³ Recently, Lacerda et al. reported that patients who consumed a Mediterranean diet supplemented with curcumin (2 g/day), tryptophan, zinc, vitamin D, quercetin, and β-glucans showed a remarkable decrease in body weight, BMI, waist circumference, lean body mass, and CRP level.⁴⁵⁴

Several studies have shown that curcumin and curcumin-containing formulations can help relieve the symptoms of osteoarthritis. A study showed that supplementation with phospholipidated curcumin (500 mg/day, twice daily) and glucosamine (500 mg/day Regenasure, twice daily) improved the Karnofsky index, the WOMAC score, and treadmill walking distance in patients with osteoarthritis of the knee.⁴⁵⁵ Also, the administration of curcuminoids with glycosaminoglycans in osteoarthritis decreased pain and joint stiffness.⁴⁵⁶ Similar outcomes in improved pain and joint stiffness were reported by Panahi et al. in 40 cases of osteoarthritis treated with 1500 mg of C3-complexed curcumin daily for 6 weeks. The treatment was also found to be safe and effective.⁴⁵⁷ A curcumin formulation was also found to be highly tolerable and increased physical performance by reducing ESR and suppressing soluble CD40 ligand (sCD40L), IL-1β, IL-6, and VCAM-1.⁴⁵⁸ In addition, administration of the curcumin formulation Meriva and glucosamine in 124 patients with osteoarthritis for 4 months showed better improvement in outcomes.⁴⁵⁹ Moreover, consumption of a water-dispersible form of curcumin, Theracurmin 180 mg/day, in 41 osteoarthritic patients produced pain relief with no adverse effects.⁴⁶⁰ A daily 1500 mg dose of the C3 curcuminoid complex in 40 osteoarthritic patients for 6 weeks markedly induced anti-inflammatory activity and produced improvements in clinical outcomes by reducing serum levels of IL-4 and hs-CRP.⁴⁶¹ Furthermore, daily administration of 1500 mg of C3 in combination with bioperine in 40 osteoarthritic patients for 6 weeks relieved disease-related symptoms by inducing antioxidant activities and suppressing oxidative stress via downregulation of MDA and upregulation of SOD and GSH.⁴⁶² Patients treated with CuraMed (containing 333 mg curcuminoids) and Curamin (containing 350 mg curcuminoids plus 150 mg boswellic acid) tolerated the treatments well, with no adverse effects, and experienced a reduction in pain-related symptoms. The major effect of CuraMed was observed in terms of physical performance tests, while the combination therapy Curamin was effective in physical performance tests and the WOMAC joint pain index. The combination treatment was better than curcuminoids alone versus placebo.⁴⁰⁴ Another study showed that Coll2-1, a specific cartilage biomarker in osteoarthritis, was downregulated with CRP after daily treatment with 252 mg of bio-optimized curcumin (Flexofytol) for 3 months in 20 patients with osteoarthritis.⁴⁶³ In addition, administration of Longvida, a solid lipid formulation of curcumin, at 800 mg/day for 90 days reduced the VAS score and the WOMAC score in osteoarthritis.⁴⁶⁴ Further, Shep et al. showed that thrice-daily curcumin (500 mg) for 28 days lowered pain and body weight in osteoarthritis versus the standard diclofenac treatment.⁴⁶⁵ Furthermore, administration of nanomicellar curcumin (80 mg/day) for 3 months reduced the VAS score, CRP, CD4⁺ and CD8⁺ Th17 cells, and B cells, and increased Treg cells in osteoarthritis.⁴⁶⁶

A randomized, controlled, double-blind clinical trial of osteoarthritis showed that patients in the curcumin intervention group had lower scores for pain and stiffness and increased physical activity scores compared to the controls.⁴⁶⁷ In addition, two independent clinical trials of osteoarthritis showed that curcumagalactomannoside treatment reduced VAS, WOMAC, and stiffness scores and increased walking performance and physical activity.^468,469 Another study demonstrated that the application of curcumin ointment twice a day on the knee reduces the severity of knee joint pain in osteoarthritis (n = 72).⁴⁷⁰ Recently, a randomized placebo-controlled clinical trial conducted by Jamali et al. showed that the application of curcumin ointment (5%) for 6 weeks remarkably improved QoL in older adults with knee osteoarthritis compared to those who applied Vaseline.⁴⁷¹ In a randomized, double-blind, Internet-based, and placebo-controlled clinical trial, curcumin (168 mg/day) with Boswellia serra extract (250 mg/day), pine bark extract (100 mg/day), and methylsulfonylmethane (1500 mg/day) for 12 weeks reduced the functional index for hand osteoarthritis score and activity impairment in patients with osteoarthritis (n = 106).⁴⁷² Recently, Atabaki et al. showed that nanocurcumin (80 mg/day) for 3 months reduced the expression of inflammation-associated miRNAs, including miRNA 16, 138, and 155, in patients with osteoarthritis.⁴⁷³ Moreover, a double-blind, randomized, and open-labeled clinical trial demonstrated that curcumin intake (1600 mg/day) along with meloxicam (15 mg/day) drastically reduced pain and inflammation (IL-1β, IL-6, and TNF-α levels) and yielded a marked increase in physical function in patients with mild-to-moderate osteoarthritis (n = 42).⁴⁷⁴ In addition, daily oral supplementation with 180 mg/day curcumin (Theracurmin) for 12 months reduced roughness in the lateral compartment of the femur, increased knee joint stiffness, and increased the Japanese knee osteoarthritis measure, Japanese orthopedic association score, and VAS score in patients with chondral diseases undergoing mosaicplasty for the knee joint (n = 23).⁴⁷⁵ However, another study showed that curcumin (160 mg/day) alone or in combination with fish oil had no remarkable effect on osteoarthritis pain in obese adults.⁴⁷⁶ Further, the administration of 1 g curcumin (Algocur) in 50 patients suffering from osteomuscular pain for 10 days showed an improvement in physical functions and decreased pain, was well tolerated, and was accompanied by no adverse effect.⁴⁷⁷

Treatment with curcumin (500 mg/day) in combination with piperine for 6 weeks suppressed MDA levels and enhanced GSH levels in pancreatitis.⁴⁷⁸ Another randomized clinical trial showed that postoperative curcumin (500 mg) effectively reduced pain and fatigue in patients who underwent laparoscopic cholecystectomy.⁴⁷⁹ In an open-label pilot study, curcumin (750 mg/day, orally) was shown to remarkably reduce serum alkaline phosphatase levels in a few patients (although the decrease was seen in other patients, it was not statistically significant) with primary sclerosis cholangitis (n = 15).⁴⁸⁰ Moreover, a double-blind randomized clinical trial showed that the application of nanomicelle curcumin (1% gel) 3 times a day effectively (p < 0.05) reduced lesion size and pain score in 24 patients with recurrent aphthous stomatitis (RAS) compared to curcumin gel alone (2%).⁴⁸¹ A randomized, single-center, single-blind clinical trial of curcumin gel (2%) showed that daily application for 180 days reduced the erythema, pain score, ulcer size, and recurrence rate in patients with RAS (n = 48).⁴⁸² In another study of curcumin gel (2%) twice-daily application remarkably reduced ulcer size and pain in 57 patients with RAS.⁴⁸³ In contrast, Kia et al. showed that patients with RAS who received 5% curcumin orabase experienced no remarkable effect on pain severity or lesion size compared to those treated with 0.1% triamcinolone acetonide.⁴⁸⁴

Administration of curcumin 500 mg per day for 2 months in 241 patients with perennial allergic rhinitis was found to improve nasal airflow and induce an immunomodulatory response by reducing nasal symptoms like sneezing, itching, and rhinorrhea and by ameliorating nasal congestion through the suppression of airflow resistance. Immunomodulation occurred via suppression of IL-4, IL-8, and TNF-α while enhancing expression of IL-10 and soluble ICAM (sICAM).⁴⁸⁵ Moreover, treatment with 100 mg of curcumin in combination with isoflavones for 6 months produced an anti-androgen effect by decreasing the level of PSA in 85 patients who did not have prostate cancer.⁴⁸⁶ Curcumin (350 mg) in combination with calendula extract (80 mg) for 1 month remarkably reduced pain and inflammatory cytokine expression in patients with chronic prostatitis or chronic pelvic pain syndrome type III.⁴⁸⁷

These studies suggest that turmeric and curcumin are potential candidate therapies for inflammatory disorders.

4.2.8. Turmeric and Curcumin in Inherited Disorders

An estimated 70,00,000 people are born annually with a congenital abnormality or inherited disorder, and the disease burden is increasing globally.⁴⁸⁸ Although certain inherited disorders have caught the attention of the World Health Organization, disease control and management remain in their infancy.⁴⁸⁸ Several clinical trials suggest the potential for curcumin in treating these diseases. A randomized clinical trial of 60 patients with FAP treated with curcumex (mixture of ginger, curcumin, and black pepper) for 8 weeks yielded a remarkable reduction in DAS, TJC, SJC, ESR, inflammation, and pain.²⁰⁴ Treatment with curcumin (3000 mg/day) for 12 months had no effect on polyp number and size in patients with familial adenomatous polyposis.⁴⁸⁹ Another study showed that presurgical curcumin (500 mg/day) with Mirtoselect (extract of Vaccinium myrtillus) reduced NF-κB and Ki-67 expression in colorectal adenomatous polyposis (n = 35).⁴⁹⁰ A randomized, double-blind, and placebo-controlled clinical trial showed that administration of FLOVOMEGA (80 g/day) containing ascorbic acid, acetyl carnitine-l-HCl, baicalin, coenzyme Q10, phospholipidated curcumin, fructose, green tea catechins, and skullcap reduced serum CK levels and improved walking distance in 29 patients with Duchenne muscular dystrophy, Facioscapulohumeral dystrophy (FSHD), or Limb girdle muscular dystrophy (LGMD).⁴⁹¹

The potential utility of curcumin in the treatment of β-thalassemia has been examined in many clinical trials. For instance, curcuminoid (500 mg/day for 12 months) remarkably reduced methemoglobin (MHb), hydrogen peroxide-induced MDA, SOD, and GPx levels in patients with β-thalassemia/Hb E.⁴⁹² Yanpanitch et al. demonstrated that curcuminoids (500 mg/day) with N-acetylcysteine (200 mg/day) and the iron chelator deferiprone (50 mg/day) for 12 months remarkably reduced iron load, oxidative stress, and blood coagulation potential, and enhanced antioxidant potential and hemoglobin levels in patients with β-thalassemia/HbE.⁴⁹³ In addition, in a double-blind, randomized, and placebo-controlled clinical trial, curcumin (1000 mg/day) reduced MDA levels and total and direct bilirubin and increased the TAC in 61 patients with β-thalassemia major.⁴⁹⁴ Moreover, a randomized double-blinded clinical trial showed that curcumin supplementation (500 mg capsules twice a day) for 12 weeks alleviated the iron load by reducing the non-transferrin-bound iron (NTBI) load and improved hepatic function by reducing ALT and AST levels in patients with β-thalassemia.⁴⁹⁵ In another study, patients with β-thalassemia/HbE treated with curcuminoids at 500 mg/day for 12 months possessed elevated levels of vitronectin, paraoxonase 1 (PON1), prothrombin, apoE, and reduced apo-A1 levels.⁴⁹⁶ In another study, 500 mg/day curcumin reduced levels of HOMA-IR, TG, TG to HDL-cholesterol ratio, and hs-CRP levels compared to both placebo and baseline values in patients with β-thalassemia major (n = 68).⁴⁹⁷ In another randomized double-blind clinical trial, curcumin (500 mg thrice a day) reduced copper, ferritin, BMI, TG, and HDL levels and increased serum zinc levels and the zinc-to-copper ratio in β-thalassemia.⁴⁹⁸ In a permuted block randomized study, curcuminoids (500 and 1000 mg/day) reduced the hypercoagulability marker D-dimer, NTBI, ROS, MDA, D-dimer, hs-CRP, TNF-α, TGF-β1, IFN-γ, IL-1β, IL-6, IL-8, serum iron, and transferrin saturation in β-thalassemia.⁴⁹⁹ Recently, a randomized, double-blind study showed that curcumin supplementation reduced serum levels of iron, ferritin, and transferrin when compared to placebo in patients with β-thalassemia intermedia.⁵⁰⁰

4.2.9. Turmeric and Curcumin in Kidney Diseases

The kidney is a vital organ required to maintain homeostasis and the most vulnerable organ affected by primary diseases affecting the kidney, including CKD, glomerulitis, nephritis, polycystic kidney disease, and kidney failure, but also from metabolic syndrome, obesity, diabetes, hypertension, and CVDs.^501−503 Several studies have shown the beneficial effects of turmeric and curcumin in treating renal disease. For example, a C. longa supplement improved the levels of the inflammatory cytokines and antioxidant capacity in CKD, suggesting the supplement may combat chronic inflammation.^504−507 Further, turmeric extract administered to patients undergoing elective coronary angiography reduced the incidence of contrast-induced nephropathy (CIN). However, this effect was statistically insignificant.⁵⁰⁸ Turmeric also remarkably alleviated oxidative stress in patients with end-stage renal disease (ESRD) undergoing hemodialysis by regulating levels of critical markers of oxidative stress such as MDA, CAT, and albumin. This study also reported that turmeric was well tolerated and did not impart any side effects.⁵⁰⁹ Another study showed that turmeric capsules can be used to treat uremic pruritus in patients with ESRD undergoing hemodialysis. Turmeric remarkably reduced one of the disease biomarkers, hs-CRP, and pruritus score without causing side effects.⁵¹⁰ Turmeric capsules were also found to reduce hematuria, proteinuria, and systolic blood pressure in refractory lupus nephritis, suggesting it can be used as an adjuvant.⁵¹¹ In a randomized clinical trial of curcumin (25 mg/kg/day) with ascorbic acid (0.075 g/kg/day), improved brachial artery FMD was observed in patients with autosomal dominant polycystic kidney disease (n = 60).⁵¹² In another study, Pivari et al. showed that 500 mg of curcumin twice a day for 3–6 months given to patients with CKD reduced their intake of carbohydrates, protein, total fiber, phosphorus, and potassium and reduced levels of inflammatory markers MCP-1, IL-4, IFN-γ, thiobarbituric acid-reactive substances (TBARS), and p-cresyl sulfate.⁵¹³ In addition, the gut bacteria Escherichia–Shigella, Enterobacter, Verrucomicrobia, and Firmicutes were depleted, and Lachnoclostridium spp., Lachnospiraceae, Lactobacillaceae spp., Prevotellaceae, and Lachnospira were enhanced in the treated patients.⁵¹³ In another study, curcumin (500 mg/day) for 15–30 days reduced urinary microalbumin, LDL-C, LPS, and caspase 3 and increased SOD1, SOD2, NADPH quinone dehydrogenase 1 (NQO-1), and IκB in diabetic patients with kidney disease.⁵¹⁴ A randomized double-blind clinical trial of curcumin (1 g/day) for 12 weeks showed an increase in catalase activity and preserved GPx activity in patients undergoing hemodialysis (n = 43).⁵¹⁵ Further, curcumin in combination with resveratrol (500 mg/day) was shown to remarkably reduce ferritin, TG, and VLDL levels and increase BMI, muscle, and bone mass in 40 patients undergoing hemodialysis.⁵¹⁶ Another clinical trial showed that daily intake of 120 mg of nanocurcumin for 3 months reduced serum IL-6 and TNF-α levels and transcript expression of these markers in the PBMCs of patients undergoing hemodialysis.⁵¹⁷ In contrast, another clinical trial showed that 1500 mg/day of curcumin for 5 days in 60 patients with CKD had no remarkable effect on disease symptoms.⁵¹⁸

4.2.10. Turmeric and Curcumin in Metabolic Disorders

The increasing prevalence of metabolic diseases seriously affects human health and is among the leading causes of morbidity and mortality worldwide.⁵¹⁹ Several risk factors, such as sedentary lifestyle, dyslipidemia, leptin resistance, insufficient adiponectin, refractory and faulty insulin production, and glucose intolerance, lead to these diseases.⁵¹⁹ Preclinical assessments of turmeric and curcumin have been performed in the context of several metabolic illnesses, including diabetes and obesity, revealing remarkable positive outcomes in prevention and treatment. For instance, turmeric formulations such as Galena, G-400, and turmeric capsules modulate the levels of critical regulators associated with T2D, including BMI, blood pressure, glucose, hemoglobin, insulin, HOMA-IR, TG, and cholesterol.^520−525 Further, C. longa extract improved vascular function in T2D by relieving clinical parameters such as carotid-femoral pulse wave velocity, left brachial-ankle pulse wave velocity, aortic augmentation pressure and index, and arterial stiffness.⁵²⁶ Further, turmeric capsules are effective for the treatment of ESRD in T2D nephropathy. The treatment remarkably modulated IL-8 and TGF-β levels and while also alleviating proteinuria, implying that turmeric could be used as an adjuvant therapy in T2D nephropathy.⁵²⁷

In a double-blind, randomized control trial comparing the efficacy of curcumin (1000 mg/day) with piperine (10 mg) versus placebo in diabetes, curcumin enhanced adiponectin and decreased leptin, TNF-α, and the leptin-to-adiponectin ratio.⁵²⁸ Administration of NCB-02 curcumin capsules (300 mg/day) in 67 patients with T2D influenced endothelial dysfunction by reducing oxidative stress markers such as MDA and endothelin-1 (ET-1) and pro-inflammatory cytokines such as IL-6 and TNF-α.⁵²⁹ Further, patients given glyburide on the first day followed by curcumin capsules for the next 10 days at 475 mg/day demonstrated improved glycemic regulation and suppressed LDL, VLDL, HDL, and triglycerides.⁵³⁰ Administration of curcuminoid extract at 300 mg/day for 3 months in 100 patients with diabetes decreased fasting blood glucose, HbA1c, insulin resistance, free fatty acids (FFAs), and triglycerides, while increasing lipoprotein lipase (LPL) levels.⁵³¹ In another study, supplementation with curcuminoids for 2 months induced an anti-diabetic effect by inhibiting adipocyte fatty acid-binding protein (A-FABP), TNF-α, and IL-6 and upregulating SOD. The amelioration of A-FABP levels by curcuminoids was also positively associated with the suppression of CRP, glucose, and FFAs in diabetes.⁵³² Moreover, the administration of six capsules of 250 mg curcuminoids was beneficial in modulating the symptoms of diabetes, improving β-cell function and increasing levels of homeostatic model assessment for pancreatic beta cell function (HOMA-β) and adiponectin, while decreasing c-peptide and insulin resistance.⁵³³ In addition, the administration of six capsules of curcuminoids (each containing 250 mg) in patients with atherogenic risk resulted in increased levels of adiponectin and decreased pulse wave velocity, leptin, uric acid, triglycerides, visceral fat, and total body fat, thereby decreasing atherogenic risks in these patients.⁵³⁴ In a randomized double-blind clinical trial of a nutraceutical tablet containing curcumin (200 mg), berberine extract (200 mg), banaba extract (40 mg), inositol (300 mg), and chromium picolinate (100 μg), researchers observed reduced FBS, postprandial blood sugar (PPBS), HbA1c, serum insulin, HOMA index, TG, TC, hs-CRP, and enhanced insulin sensitivity in patients with fasting dysglycemia.⁵³⁵ Dietary supplementation with an enriched bread containing curcumin (Meriva) (228 mg/day) and phytosterol (2.3 g/day) was shown to reduce LDL-C, LDL-P number, TC, TC/HDL-C ratio, and CVD risk score compared to placebo in patients with hypercholesterolemia.⁵³⁶

Curcuminoids supplementation (500 mg/day) with piperine (5 mg/day) was demonstrated to reduce serum glucose, HbA1c, c-peptide, ALT, and AST in T2D.⁵³⁷ Furthermore, phospholipidated curcumin (500 mg) twice daily supplementation reduced macular edema and ocular thickness while improving visual acuity and demonstrating stable disease in patients with T2D-associated macular edema (12 eyes from 11 patients).⁵³⁸ Another study showed that the administration of polyvinylpyrrolidone-hydrophilic curcumin formulation (20% curcumin) via 2 capsules/day reduced the central retinal layer in patients with T2D-associated macular edema (n = 73).⁵³⁹ Furthermore, the treatment of patients at high risk of developing diabetes (impaired fasting glucose or glucose tolerance) with 1000 mg/day curcumin alone (n = 15) or with 2000 mg/day fish oil tablets (containing long-chain polyunsaturated fatty acids) for 12 weeks resulted in remarkably reduced triglyceride levels compared to placebo-controlled patients.⁵⁴⁰ This study also showed that treatment with curcumin alone remarkably improved insulin sensitivity.⁵⁴⁰ The same group also demonstrated that 180 mg/day curcumin (Meriva) for 12 weeks remarkably reduced glycogen synthase kinase-3 beta (GSK-3β), islet amyloid polypeptide, insulin resistance, and the risk of developing Alzheimer’s disease in patients at high risk of developing diabetes.⁵⁴¹ Curcumin (4 g/day) supplementation for 2 days improved the detection of amyloid spots in the retina of patients with Alzheimer’s disease.⁵⁴²

In another study, administration of 3 g/day curcuminoids for 6 months was shown to decrease atherogenic risk by reducing pulse wave velocity, leptin, TG, HOMA-IR, uric acid, visceral fat, and total body fat and inducing adiponectin in patients with type II diabetes mellitus (n = 240).⁵³⁴ Moreover, in a randomized, double-blind, placebo-controlled trial conducted by Adibian et al., with 500 mg/day curcumin thrice daily supplementation for 10 weeks reduced serum triglycerides and hs-CRP and enhanced adiponectin levels in patients with T2D (n = 25) compared to patients who received placebo.⁵⁴³ This study also indicated that curcumin effectively reduced the complications of T2D by reducing triglycerides and inflammatory markers.⁵⁴³ In addition, oral administration of curcumin reduced mean body weight, BMI, waist circumference, and FBS in 53 patients with T2D.⁵⁴⁴ Further, curcumin (Theracurmin) administration of 180 mg/day for 6 months reduced TG and γ-GTP in patients with non-insulin-dependent diabetes (n = 33).⁵⁴⁵ Nanocurcumin 80 mg/day for 12 weeks decreased FPG, insulin, TG, TC, LDL-C, VLDL-C, TC/HDL-C, hs-CRP, and MDA and increased TAC and nitrite levels in patients with T2D undergoing hemodialysis.⁵⁴⁶ Similar results in FPG, insulin, TG, TC, LDL-C, and enhanced levels of GSH, TAC, and insulin sensitivity were seen when patients with diabetic foot ulcers (n = 60) were treated with 80 mg/day of nanocurcumin.⁵⁴⁷ Furthermore, a double-blind, randomized, and placebo-controlled trial of curcuminoids with piperine for 12 weeks showed a reduction in MDA, TC, non-HDL-C, and lipoprotein A and enhanced TAC and SOD levels in T2D (n = 118).^548,549 The administration of curcumin (1 g/day) for 12 weeks suppressed MDA levels and enhanced PPARγ and TAC in patients with T2D and coronary artery disease.⁵⁵⁰

Apart from these, a couple of clinical studies have shown the efficacy of curcumin in improving the symptoms of diabetic microangiopathy. Subjects with diabetic microangiopathy received 1 g/day of Meriva for 4 weeks. The treatment was well tolerated and improved the disease condition by reducing clinical symptoms like skin flux in the foot surface and edema and improving venoarteriolar response and PO₂, thus achieving better oxygen diffusion.⁵⁵¹ In addition, the supplementation of 200 mg of curcumin (Meriva formulation) per day in combination with standard therapy achieved optimum tolerability and was shown to improve visual acuity, venoarteriolar response, and decrease peripheral edema in patient.⁵⁵²

MetS is a condition defined by insulin resistance, high blood pressure, and elevated glucose, cholesterol, and triglyceride levels. It is associated with the release of various inflammatory cytokines. Several studies have shown that turmeric extract supplementation reduces BMI, body weight, waist circumference, TG, TC, LDL-C, VLDL, and CRP and increases HDL in patients with MeS.^553−557 Panahi et al. showed that administration of 1 g C3 curcumin complex combined with piperine for 8 weeks in patients with MetS was safe and well tolerated and remarkably suppressed proinflammatory cytokines like TNF-α, IL-6, TGF-β, and MCP-1, thus ameliorating the symptoms of excessive cytokine production in these patients.⁷⁶ Serum adiponectin and leptin are altered in MetS. Curcumin 1 g/day in combination with piperine decreased leptin and increased adiponectin levels in MetS, which may lead to amelioration of insulin sensitivity.⁵⁵⁸ In addition, the consumption of curcumin and its phospholipid-complexed formulation by 120 patients at doses of 1 g and 200 mg per day, respectively, induced pro-oxidant/anti-oxidant balance (PAB) in the curcumin-treated group.⁵⁵⁹ Further, treatment with lecithinized curcumin at 1 g per day had no effect on serum vitamin E in MetS.⁵⁶⁰ The dosage of curcuminoids at 1 g/day for 8 weeks was safe and effective and induced BMI, and SOD and decreased hs-CRP, MDA, glucose, HbA1c, SBP, and diastolic pressure (DB).⁵⁶¹ The administration of curcuminoids (1 g/daily for 8 weeks) was also found to be effective in reducing total lipids like cholesterol and triglycerides in MetS.⁵⁶² A clinical trial conducted by Dizaji et al. showed that curcumin (1 g/day) and a phytosomal formulation of curcumin (1 g/day) increased the activity of aryl esterase, which has cardioprotective effects in patients with MetS.⁵⁶³ Supplementation with curcumin at 1 g/day for 6 weeks remarkably reduced the intake of saturated fatty acids in patients with metabolic syndrome (n = 40). This study also showed that curcumin and/or phospholipidated curcumin reduced cholesterol and fat intake and increased zinc and vitamin C intake, though the changes were not statistically significant.⁵⁶⁴ Another study showed that curcumin (1 g/day) and phospholipidated curcumin (1 g/day) supplementation for 6 weeks improved serum zinc levels in 120 patients with MetS.⁵⁶⁵ In another study, nanocurcumin alone or in combination with aerobic exercise reduced serum levels of IL-6, MDA, and hs-CRP and increased IL-10, BDNF, and TAC in patients with MetS.⁵⁶⁶ Nanocurcumin 80 mg/day for 12 weeks was also shown to reduce triglyceride levels and HOMA-β in patients with MetS.⁵⁶⁷ Recently, nanomicelle curcumin (80 mg/day) supplementation for 12 weeks remarkably reduced MDA levels and improved adiponectin and TAC in patients with metabolic syndrome (n = 50).⁵⁶⁸ In contrast, phosphatidylcholine curcumin (1000 mg/day) had no remarkable effect on patients with MetS.⁵⁶⁹ In addition, a double-blind, randomized clinical trial showed that curcuminoids or phospholipidated curcuminoids had no remarkable effect on sleep duration in patients with MetS (n = 109) compared to those who received a placebo comprising lactose and starch.⁵⁷⁰ Further, in a randomized clinical trial, the administration of phospholipidated and unformulated curcumin produced no remarkable effect on patients with MetS, but measures of anxiety showed a reduction in severity in the treatment group versus the placebo group.⁵⁷¹

NAFLD is the most common liver disease. It is characterized by excessive hepatic accumulation of ectopic lipids.⁵⁷² Turmeric alone and in combination with chicory seeds were found to improve the clinical parameters associated with obesity in NAFLD, such as BMI, waist circumference, ALP, and HDL-C.^573−576 In addition, turmeric supplementation improved glucose, insulin, HOMA-IR, and leptin levels in NAFLD.⁵⁷⁷ Curcumin has also proven its potential for reducing the symptoms of NAFLD. For example, a study demonstrated the potential benefit of curcumin by providing 500 mg/day of curcumin (corresponding to 70 mg curcuminoids), demonstrating a decrease in BMI and liver fat along with a reduction in lipids (such as TC, LDL-C, and triglycerides), AST, and ALT. Treatment also reduced levels of glucose and glycated hemoglobin in these patients. The treatment was also found to be safe and well tolerated.⁵⁷⁸ In another study, treatment with an amorphous disperse formulation of curcumin (500 mg/day) for 8 weeks reduced liver fat content, BMI, LDL-C, TG, AST, ALT, glucose, and glycated hemoglobin in NAFLD.⁵⁷⁹ Additionally, 1 g/day of curcumin for 8 weeks in NAFLD was found to be safe, well tolerated, and decreased TC, LDL-C, triglycerides, non-HDL-C, and uric acid.⁵⁸⁰ The same dosage of curcumin was also found to reduce BMI, AST, ALT, and liver fat in these patients.⁵⁸¹ In addition, the evaluation of different clinical parameters showed that the supplementation of curcumin (1.5 g/day) effectively reduced the fibrosis score in NAFLD when the fibrosis-4 and AST platelet ratio index methods were used; however, the differences were insignificant when BMI and the NAFLD fibrosis score were used.⁵⁸² In a clinical trial conducted by Panahi et al., the administration of 1500 mg/day of a phospholipidated formulation of curcumin remarkably reduced disease severity, BMI, TC, LDL-C, HDL-C, non-HDL-C, serum uric acid levels, portal vein diameter, liver size, and enhanced portal vein flow in patients with NAFLD.⁵⁸³ Moreover, oral supplementation of 1500 mg/day curcumin for 12 weeks reduced hepatic fibrosis and serum levels of cholesterol, glucose, and ALT in patients with NAFLD (n = 27) compared to placebo controls (n = 25). This study also showed that curcumin markedly reduced anthropometric indices, the lipid profile, insulin resistance, and hepatic steatosis compared to baseline levels in these patients.⁵⁸⁴

Oral supplementation of 80 mg/day of nanocurcumin for 3 months reduced fatty liver, waist circumference, transaminases, FBS, the fasting blood insulin, glycated hemoglobin, TG, TC, LDL, HOMA-IR, TNF-α, hs-CRP, and IL-6 and increased HDL, quantitative insulin sensitivity check index, and nesfatin levels.⁷⁵ A randomized double-blind pilot clinical trial showed that phospholipid curcumin (250 mg/day) supplementation for 8 weeks reduced the serum levels of 3-hydroxyisobutyrate, 3-methyl-2-oxovaleric acid, kynurenin, succinate, citrate, α-ketolgutarate, methylamine, trimethylamine, hippurate, indoxyl sulfate, chenodeoxycholic acid, lithocholic acid, and taurocholic acid in patients with NAFLD (n = 58).⁵⁸⁵ A randomized clinical trial of curcumin (500 mg/day) plus piperine (5 mg/day) supplementation for 12 weeks reduced hematocrit, ESR, AST, ALT, ALP, cholesterol, iron, hemoglobin, and LDL levels and enhanced total iron binding capacity in patients with NAFLD (n = 35).⁵⁸⁶ Mirhafez et al. showed that oral administration of phytosomal curcumin (500 mg/day) with piperine (5 mg/day) for 8 weeks reduced the PAB levels in patients with NAFLD (n = 24) compared to placebo controls (n = 23).⁵⁸⁷ The same group also showed that oral administration of phytosomal curcumin (250 mg/day) for 8 weeks remarkably decreased leptin levels and increased adiponectin and HDL in patients with NAFLD (n = 33) compared to placebo controls (n = 32).⁵⁸⁸ In another study, Saadati et al. demonstrated that supplementation with 500 mg of curcumin (n = 25) 3 times a day remarkably reduced hepatic fibrosis and NF-κB in patients with NAFLD compared to placebo (n = 25).⁵⁸⁹ Furthermore, several studies have shown that curcumin, either alone or in formulation, remarkably reduced AST, ALT, GGT, disease severity, waist circumference, and BMI in NAFLD.^590−594

Obesity is a major public health concern associated with premature mortality and is linked with cardiovascular disease, diabetes, and even cancer.⁵⁹⁵ Several clinical studies have proven the efficacy of turmeric and curcumin in the management of obesity. For example, administration of turmeric alone or as a dietary supplement in formulations reduces weight, BMI, waist and hip circumference, TC, TG, LDL-C, and CRP and increases HDL-C and insulin levels in obese patients.^596−600

Administration of a hot water extract of curcumin modulated inflammatory and obesity markers, including CRP, TNF-α, IL-6, s-VCAM-1, glucose, HbA1c, TG, and HDL-C and improved SF-36 and POMS scores for mental health.⁶⁰¹ This study also showed that water extract of C. longa improved inflammatory status and general health of overweight/obese patients with hypertension.⁶⁰¹ In another study, administering turmeric (500 mg/day) for 10 weeks resulted in reduced BMI, waist circumference, hip circumference, and increased HDL and insulin levels in 60 obese/overweight women.⁷⁷ Consistent with this, 1 g/day of curcuminoids for a month in obese patients induced immunomodulatory effects by reducing the levels of IL-1β, IL-4, and VEGF.⁷⁹ A daily dose of 500 or 750 mg of curcumin for 12 weeks reduced lipid peroxidation, oxidized LDL, and protein carbonyls, suggesting the potential ability of curcumin to inhibit oxidative stress in obesity.⁶⁰² Further, 1 g/day of curcumin for a month was safe and well tolerated with no adverse side effects and induced remarkable effects on lipid profiles by suppressing serum triglycerides.⁶⁰³ Furthermore, a study on 30 obese patients showed that administration of 1 g curcuminoid C3 complex plus piperine remarkably reduced serum PAB; however, no remarkable effect was observed on anti-heat shock protein 27 (anti-Hsp27) and antioxidized LDL (antioxLDL) levels.⁶⁰⁴ In another study, resveratrol (100 mg) and curcumin (50 mg) in combination reduced postprandial VCAM1 levels in older adults with abdominal obesity. However, this study also showed that the resveratrol and curcumin therapy did not alter circulating inflammatory markers, including IL-6, IL-8, or monocyte chemoattractant protein-1 levels.⁶⁰⁵

Longvida (160 mg/day) with or without fish oil improved memory in older adults with obesity.⁶⁰⁶ Studies have also showed that treatment with curcumin alone or in combination with fish oil for 16 weeks remarkably reduced subjective memory complaints, cerebral artery stiffness, and enhanced vigor in older patients with obesity.^607,608 In a randomized, double-blind clinical trial, oral administration of bioavailable CurQfen 500 mg/day for 12 weeks in obese men (n = 22) reduced homocysteine levels and increased HDL levels compared to placebo controls.⁶⁰⁹ Moreover, a double-blind, randomized clinical trial by Cicero et al. showed that phytosomal curcumin (200 mg curcumin, 480 mg phosphatidylcholine, 120 mg phosphatidylserine, and 8 mg piperine) of 800 mg/day for 8 weeks effectively reduced the fatty liver index (FLI), HOMA-IR, glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase, non-LDL-C, and TG in obese patients with metabolic syndrome (n = 40) compared to placebo (n = 40).⁶¹⁰ This study also showed that FLI, FPG, FPI, GGT, HOMA-IR, hepatic steatosis index, lipid accumulation product, and non-LDL-C levels were remarkably decreased and HDL-C levels were increased upon treatment with phytosomal curcumin versus baseline levels.⁶¹⁰ In addition, a randomized, double-blind, placebo-controlled trial of curcumin (500 mg/day) showed reduced weight, BMI, and fasting blood glucose in patients with obesity.⁶¹¹ The study also showed that curcumin along with aerobic exercise has more potential benefits than curcumin alone. Curcumin with aerobic exercise was shown to reduce waist circumference, waist-to-hip ratio, HOMA-IR, serum insulin, CRP, LDL/HDL, and TC/HDL, and increase serum HDL cholesterol.⁶¹¹ Recently, Karandish et al. showed that supplementation with curcumin alone (500 mg/day) or with zinc (30 mg/day) for 90 days reduced FPG, 2 h postprandial glucose, HbA1c, insulin resistance, and insulin in patients with obesity and prediabetes (n = 82). Furthermore, curcumin with zinc remarkably reduced BMI in these patients.⁶¹² The same group later showed that curcumin with or without zinc reduced TC, TG, LDL, and non-HDL and increased HDL.⁶¹³ Further, a randomized crossover clinical trial showed that curcuminoid administration (1 g/day) with bioperine (10 mg/day) for 30 days remarkably decreased serum triglyceride levels in obese patients.⁶⁰³ Another study showed that daily administration of curcuminoids downregulated monocyte chemoattractant protein 1 and monocyte inhibitory factor in obese individuals.⁶¹⁴ In addition, a randomized trial of curcuminoids (1000 mg/day) with bioperine (10 mg/day) showed a reduced serum zinc-to-copper ratio in patients with obesity.⁶¹⁵ Oral supplementation of curcumin (110 mg/day) with alendronate (5 mg/day) in postmenopausal women with osteoporosis (n = 60) reduced osteocalcin and increased bone-specific alkaline phosphatase, C-terminal cross-linking telopeptide of type I collagen (CTx), and bone mineral density (BMD).⁶¹⁶

Overall, these clinical trials showed that curcumin and turmeric alone, in formulations and/or in combination with other compounds, effectively prevent the incidence, prevalence, and disease burden of metabolic disorders.

4.2.11. Turmeric and Curcumin in Neurological Disorders

Neurological disorders arise due to impairment of the central nervous system and are mostly irreversible due to the limited regenerative capacity.⁶¹⁷ Various studies have evaluated the efficacy of turmeric and curcumin in treating neurological disorders. For example, a study showed that administration of a 500 mg turmeric-based supplement reduced the severity of symptoms in women with fibromyalgia.⁶¹⁸ Another study showed that 2 or 4 g of curcumin C3 complex in Alzheimer’s disease for 24 weeks was well tolerated.⁶¹⁹ Moreover, in a randomized double-blind clinical trial, curcumin (600 mg/day) reduced the levels of advanced oxidation protein products and increased amyotrophic lateral sclerosis (ALS) functional rating scale (ALS-FRS-r) and ferric reducing ability (FRAP) stable scores in patients with ALS (a progressive neurodegenerative disorder).⁶²⁰ A pilot clinical study showed that nanocurcumin (80 mg/day), as an adjunct to riluzole therapy, increased survival in patients with ALS.⁶²¹ Curcumin powder supplementation was shown to be safe and effective and improved QoL in a 15-year-old Caucasian girl suffering from Déjérine–Sottas disease, with the dose of 50 mg/kg/day for the first 4 months, followed by 75 mg/kg/day, was shown to be safe and effective. It also improved pulmonary function and hand and foot strength.⁶²² Daily treatment with 180 mg of curcumin for 18 months in 40 patients improved memory and concentration and suppressed amyloid and tau proteins.⁶²³ In another study, the administration of a solid lipid formulation of curcumin, Longvida 400 mg, improved memory function and attentive performance in patients and reduced TC and LDL-c levels.⁶²⁴ In addition, oral supplementation of 80 mg/day curcumin for 12 weeks remarkably downregulated transcript expression of cFLIP in patients with human lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (n = 20).⁶²⁵ Further, a randomized, single-center, open-label clinical trial showed that administration of curcumin (1500 mg/day) as adjuvant therapy remarkably reduced systolic blood pressure, markedly increased muscle power, and improved stroke-specific QoL (SSQoL) questionnaire domains, such as energy, extremity function, mobility, productivity, and thinking process in patients with postischemic stroke.⁶²⁶

Another study showed that nanocurcumin with omega-3 fatty acids prevented migraine complications by reducing the incidence of attacks and serum ICAM levels.⁶²⁷ Moreover, a randomized double-blind clinical trial showed that administration of nanocurcumin (80 mg/day) with ω-3 fatty acids (2500 mg/day) for 2 months reduced the frequency of headache and both mRNA expression and serum levels of the inflammatory marker TNF-α in patients with migraine (n = 74).⁶²⁸ Intake of 500 mg/day curcumin for 8 weeks reduced calcitonin gene-related peptide and headache severity in migraine patients.⁶²⁹ Soveyd et al. demonstrated that curcumin supplementation with ω-3 fatty acids reduced the frequency of headache attacks and serum levels of ICAM-1 in patients with migraine.⁶²⁷ In a pilot clinical study, the oral administration of curcumin (80 mg/day) alone or in combination with ω-3 fatty acids (2500 mg/day) twice a day reduced IL-6 mRNA and serum levels of IL-6 and hs-CRP in patients with migraine (n = 40).⁶³⁰ In addition, supplementation of curcumin (80 mg/day) in combination with ω-3 fatty acids reduced both mRNA and circulating levels of COX-2 and iNOS and reduced the frequency of attacks, severity of pain, and headache duration among migraineurs.⁶³¹ The same group showed that nanocurcumin 80 mg/day reduced VCAM in migraine.⁶³² Episodic migraine patients treated with nanocurcumin (80 mg) for 2 months showed downregulated expression and serum levels of pentraxin 3, indicating the therapeutic efficacy of curcumin in migraine.⁶³³ Later, the same group showed that nanocurcumin (80 mg) supplementation for 2 months reduced IL-17 transcript expression in PBMCs and serum levels of IL-17 in patients with migraine (n = 40).⁶³⁴ In another study, Honarvar et al. demonstrated that nanocurcumin (80 mg/day) in combination with ω-3 fatty acids (2.5 g/day) remarkably reduced headache attack frequency and neuroinflammation via downregulating serum IL-β levels in patients with migraine.⁶³⁵ Moreover, nanocurcumin (80 mg/day) with coenzyme Q10 (300 mg/day) for 8 weeks remarkably reduced the frequency, severity, and duration of migraine attacks.⁶³⁶ Supplementation with 80 mg/day of nanocurcumin reduced serum MCP-1 levels as well as headache attack frequency, severity, and duration in obese and overweight patients with migraine (n = 22) compared to placebo (n = 22).⁶³⁷ In another study, Dolati et al. demonstrated that the treatment of multiple sclerosis with nanocurcumin (80 mg/day) reduced the frequency of Th17 cells, IL-17, and RORγt.⁶³⁸ The same group showed that nanocurcumin (80 mg/day) increased the frequency of Treg cells in patients with multiple sclerosis (n = 25).⁶³⁹ This study also showed that PBMCs isolated from the nanocurcumin-treated group possess increased levels of secreted TGF-β and IL-10 and increased transcript expression of TGF-β, IL-10, and forkhead box P3 (FoxP3).⁶³⁹ In addition, patients with relapsing multiple sclerosis treated with curcumin (500 mg twice a day) with IFN-β-1a (3 × 44 μg/wk) showed a reduction in combined unique active lesions.⁶⁴⁰ The miRNAs miR-16, miR-17-92, miR-27, miR-29b, miR-126, miR-128, miR-132, miR-155, miR-326, miR-550, miR-340, miR-15a, miR-19b, miR-106b, miR-320a, miR-363, miR-31, miR-181c, miR-150, and miR-599 are deregulated in multiple sclerosis, compared to healthy adults, and treatment with nanocurcumin (80 mg/day) for 6 months was shown to restore expression of these miRNAs, thereby reducing the frequency of demyelinating inflammatory conditions in these patients.⁶⁴¹

Additionally, treatment of ME/CFS (n = 76) using nutraceuticals with anti-inflammatory, oxidative, and nitrosative stress therapies containing curcumin reduced the IgM-mediated autoimmune response to oxidative-specific epitopes and nitroso-adducts, fibromyalgia, the fatigue syndrome rating score, and the severity of illness.⁶⁴² A randomized, triple-blind, placebo-controlled pilot study showed that administration of curcumin (80 mg/day) in Parkinson’s disease (PD) (n = 30 patients) reduced scores on the Movement Disorder Society-sponsored revision of the Unified PD Rating Scale Part III, indicating improved QoL.⁶⁴³ In a parallel group randomized and controlled clinical trial, curcumin 1200 mg/day was provided as part of an anti-inflammatory diet including ω-3 fatty acids, coenzyme Q10, N-acetyl cysteine, tocopherols, α-lipoic acid, green tea extract, vegetable based protein powder, and minerals to remarkably decrease proinflammatory composite score, serum levels of IFN-γ, IL-6, IL-1β, and CRP and increase the tryptophan-to-large neutral amino acid ratio in patients with spinal cord injury.⁶⁴⁴ Furthermore, in a controlled clinical trial, curcumin 110 mg/kg/day for 6 months improved BMD indicators in the lumbar, neck, femoral, and hip regions in patients with spinal cord injury (n = 100).⁶⁴⁵

In another study, nanocurcumin (80 mg/day) for 8 weeks reduced glycated hemoglobin, FBS, total neuropathy score, and total reflex score, indicating a reduction in the severity of sensorimotor neuropathy in patients with T2D (n = 40) compared to placebo controls (n = 40).⁶⁴⁶ Oral administration of 80 mg/day curcumin alone or with exercise reduced fasting blood glucose, glycated hemoglobin, and insulin levels in patients with T2D (n = 40).⁶⁴⁷ In another study, 80 mg/day of nanocurcumin for 8 weeks reduced depression and anxiety in 80 patients with T2D-associated neuropathy.⁶⁴⁸ In addition, administration of 500 mg/day curcuminoids with 5 mg/day piperine for seven days remarkably reduced leptin levels, IL-6, TNF-α, MCP-1, CRP, SOFA score, NUTRIC score, and APACHEII score in patients with traumatic brain injury.^649,650

Together, these results suggest that supplementation with curcumin aids in the prevention of a wide variety of neurological diseases, ameliorates disease progression, and reduces disease burden and morbidity.

4.2.12. Turmeric and Curcumin in Psychotic Disorders

Psychotic disorders refer to an abnormal state of mind and a constellation of symptoms that reflect a disturbance in cognitive and perceptual functions, impeding regular activities and debilitating QoL.⁶⁵¹ The bioactive ingredient curcumin and its formulation have shown results in clinical trials. Depression-related disorders are a multifactorial disease associated with depressed mood, lack of energy, poor concentration, sleep disturbances, and suicidal thoughts in affected individuals.⁶⁵² It is a common disorder affecting >300 million people worldwide.⁶⁵³ In a randomized pilot study, curcumin (180 mg/day) for 8 weeks as an add-on therapy enhanced working memory and lowered IL-6 and hs-CRP levels in patients with schizophrenia (n = 12).⁶⁵⁴ Another study showed that curcumin (3 g/day) for 24 weeks reduced the Calgary Depression Scale for Schizophrenia scores and increased Positive and Negative Symptoms Scale (PANSS) scores in patients with chronic schizophrenia.⁶⁵⁵ Moreover, administration of nanocurcumin 160 mg/day for 16 weeks reduced the PANSS negative subscale score while increasing the PANSS positive subscale score and clinical response rate in 56 patients suffering from chronic schizophrenia.⁶⁵⁶

Accumulating evidence indicates the efficacy of curcumin in ameliorating the severity and symptoms of depressive disorders. A study by Kanchanatawan et al. analyzed the effect of adjunctive treatment with 500–1500 mg/day of curcumin in 65 patients with major depressive disorder for 12 weeks, showing an improvement in depressive symptoms as observed through the Montgomery–Asberg Depression Rating Scale. In the same study, curcumin decreased the Hamilton Anxiety Rating Scale (HAM-A) more in males than females, suggesting that it was more effective in males. The treatment was also found to be safe and well tolerated.⁶⁵⁷ Lopresti et al. showed the modulation of several biomarkers associated with antidepressive mechanisms by curcumin treatment. For instance, administration of 1 g of curcumin daily for 8 weeks upregulated urinary thromboxane B2, substance P (SP), and plasma concentrations of endothelin-1 and leptin.⁶⁵⁸ Another randomized double-blind crossover study investigated the effect of curcumin supplementation on anxiety and depression in obese subjects. The subjects were given placebo and curcumin (1 g/day) for a month, and the groups were crossed over for another month of treatment. Curcumin supplementation had no effect on the Beck Depression Inventory scale, although a reduction in Beck Anxiety Inventory scores was observed, suggesting that curcumin may affect anxiety in obese individuals.⁶⁵⁹ The efficacy of curcumin was also investigated in major depressive disorder. In this study, the patients were treated with placebo and curcumin (500 mg daily and 1 g twice daily) and curcumin in combination with saffron (250 mg and 15 mg twice daily) for a period of 12 weeks. All treatment groups showed no adverse events, and the treatment decreased the symptoms associated with depression and anxiety.⁶⁶⁰ Inflammatory cytokines are upregulated in depressive patients. Administration of 1000 mg/day curcumin powder in patients with major depressive disorder for 6 weeks decreased inflammation by suppressing cytokines such as IL-1β and TNF-α and the stress hormone cortisol. It also induced plasma BDNF levels, suggesting its potential benefit in improving depressive disorders.⁶⁶¹ Further, administration of 1 g of curcumin (BCM-95) for 8 weeks in patients with major depressive disorder showed improvement in mood-related symptoms with no adverse events, with a greater effect observed in the subgroup of patients with atypical depression.⁶⁶² In another study, the administration of curcuminoids combined with piperine at a dose of 1000 mg/day for 6 weeks was shown to reduce anxiety and depressive symptoms. The treatment was safe and effective.⁶⁶³ Moreover, the administration of 1 g of curcumin alone or in combination with fluoxetine in depressive patients for 6 weeks was found to be an effective treatment that was safe and well tolerated.⁶⁶⁴ In addition, Bergman et al. evaluated the efficacy of 500 mg of curcumin daily in depressive patients for 5 weeks and showed improvement in the symptoms associated with the disease with no adverse effects.⁶⁶⁵

4.2.13. Turmeric and Curcumin in Oral Diseases

Oral diseases comprise a large number of disorders of the oral cavity and various potentially malignant disorders such as OLP, oral submucous fibrosis (OSF), oral mucositis, periodontitis, and dental caries.³⁹ Turmeric was found to have a potential role in treating oral diseases. For instance, when a turmeric chip was used as a drug delivery agent in combination with root planing (SRP) and scaling to treat a patient suffering from chronic periodontitis, it led to an improvement in the clinical parameters, such as the PI, GI, probing pocket depth (PPD), and relative attachment level (RAL). Further, the efficacy of the turmeric chip was comparable with that of the standard antiseptic, chlorhexidine (CHX) chip.⁶⁶⁶ Mouthwashing with turmeric has been shown to reduce the PI, microbial count, and GI and increase IL-1β levels in patients with gingivitis.^667−670 Several studies have demonstrated the potential of curcumin and/or its formulations in the management of various oral diseases. The administration of 3.6 g/day of curcumin in 213 patients with OLP showed a better clinical response, and the treatment was safe and well tolerated.⁶⁷¹ In addition, a dose of 1 g of curcumin for 7 days was safe and well tolerated in 28 patients with OLP.⁶⁷² A higher dose of curcuminoid C3 complex at 6 g/day for 12 days was efficacious in the management of OLP, and the treatment was found to suppress erythema, ulceration, and other signs and symptoms of the disease.⁶⁷³ However, a study by Amirchaghmaghi et al. showed that 2 g daily dose of curcumin had no detectable effect in OLP.²⁹⁰ Interestingly, administration of 500–6000 mg/day of C3 complex and a follow-up period of 1–5 years revealed that symptom intensity was effectively reduced in OLP.⁶⁷⁴ Thus, more studies on the effect of curcumin in the prevention and treatment of this disease are needed. The usage of curcumin mouthwash in patients with oral mucositis was shown to be safe and well tolerated with no report of adverse events.⁶⁷⁵ In patients with dental caries and dental blocks, dipping the dental blocks (incorporated blocks were removed after 4 days) for 5 min in 1500 μg/mL curcumin and curcumin plus light treatment reduced microbial biofilm formation and suppressed the viability of Streptococci, thus suggesting curcumin could be used for the management of dental caries.⁶⁷⁶ Curcumin disinfection yielded the highest shear bond strength in extracted caries-affected dentin (n = 75) compared to other photosensitizers such as methylene blue, silver diamine fluoride, ozone, and chlorhexidine.⁶⁷⁷ In a pilot study, chewing curcumin gum for 30 min released higher amounts of curcumin and facilitated the direct absorption of curcumin from the buccal mucosa to the blood in healthy subjects. This study also showed that a concurrent increase in serum curcumin levels lowered serum levels of CXC motif chemokine ligand 1 (CXCL1) and TNF-α, indicating potential activity in the prevention of oral cavity cancers.⁶⁷⁸ Moreover, a randomized clinical trial showed the utility of curcumin as an obturation material in deciduous teeth with a success rate of 61.5% among a total of 64 children undergoing root canals; however, this rate was less than the success rates of calcium chloride (93.8%) and metapex (100%).⁶⁷⁹ In a double-blind, randomized clinical trial, nanocurcumin (80 mg/day) reduced the modified GI (MGI) and papillary bleeding index in patients with gingivitis and mild periodontitis (n = 47) compared to those who received placebo.⁶⁸⁰ Curcumin mouthwash was also shown to be effective in gingivitis due to its anti-inflammatory properties, suggesting its potential as an adjunct therapy for the management of gingivitis.⁶⁸¹ Labban et al. showed that mouth rinsing with 100,000 UI/mL curcumin for 60 s followed by photodynamic therapy reduced the overall CFU/mL score and decreased the occurrence of Candida albicans, C. tropicalis, C. glabrata, and denture stomatitis in patients who were habitual smokers (n = 15).³⁸⁸ In a pilot study, the application of 1% curcumin gel reduced the growth of oral bacteria, including Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, and Capnocytophaga, in patients with periodontitis (n = 25).⁶⁸² In another study, supplementation with curcumin nanoparticles for 15 days reduced Porphyromonas gingivalis and increased Veillonella parvula and Actinomyces spp. in periodontitis.⁶⁸³ Moreover, a randomized, single-blinded clinical trial of gingival irrigation with 1% curcumin solution on days 7, 14, and 21 for 6 months reduced the bleeding score, PI score, and PPD in patients with chronic periodontitis.⁶⁸⁴ Studies have shown that the application of curcumin gel/strips effectively reduces CAL gain, GI, PI, PPD, SBI, SOD, RAL, and CFU in periodontitis.^685−688 In a randomized controlled split-mouth trial, Ivanaga and colleagues showed that irrigation with curcumin in the presence or absence of LED irradiation in patients with chronic periodontitis and T2D remarkably reduced the PI after 90–180 days of follow-up. This study also showed that curcumin irrigation alone or with LED irradiation reduced probing depth and clinical attachment gain, although the differences were not statistically significant.⁶⁸⁹ Recently, Rahalkar et al. showed that the application of curcumin gel followed by scaling and root planning (SRP) of the periodontal pocket remarkably reduced the PI in patients with periodontitis (n = 15) compared to patients who underwent SRP alone.⁶⁹⁰ In a split-mouth pilot clinical trial, the application of curcumin mucoadhesive film (0.5%) remarkably reduced postsurgical pain and swelling and reduced the intake of analgesics in patients with periodontitis.⁶⁹¹ In another study, Al-Aksar et al. showed that supplementation with curcumin (500 mg) after surgical periodontal therapy in patients with stage 3/grade C periodontitis reduced pain and postoperative discomfort, though the differences were not remarkable between the curcumin and mefenamic acid (standard) treatment groups.⁶⁹² Curcumin was found to be effective in patients having orthodontic implants by reducing plaque accumulation with no side effects.⁶⁹³ The curcumin solution was also found to reduce oral microbial growth in 27 patients, suggesting the potential of curcumin as an oral antimicrobial agent.⁶⁹⁴ In addition, curcumin alone or in combination with photodynamic therapy reduced the bacterial population in the treatment group.^695,696 Similarly, curcumin in combination with photodynamic therapy and curcumin plus SDS with photodynamic light reduced the viability and survival of bacteria like S. mutans in orthodontic patients, suggesting that curcumin could promote oral decontamination.⁶⁹⁷ Further, patients treated with 25 and 100 mg/L of natural curcumin (prepared in 99.9% absolute ethanol and 0.1% DMSO) after photodynamic inactivation (PDI) exhibited a decreased oral microbial load even after 24 h compared to the other therapy in the study.⁶⁹⁸ Thus, these studies suggest curcumin is a potential candidate therapy for various diseases of the oral cavity.

4.2.14. Turmeric and Curcumin in Pulmonary Disorders

Pulmonary disorders are associated with ailments affecting the human respiratory system and can lead to several other complications.⁶⁹⁹ α1-Antitrypsin-low-density lipoprotein (AT-LDL) is an oxidized form of LDL mostly found in atherosclerotic patients and might trigger other CVDs. Interestingly, in a study of 180 mg of curcumin per day in 39 patients for 24 weeks, researchers observed inhibition of AT-LDL levels, which might be beneficial in preventing cardiovascular events in chronic obstructive pulmonary disease (COPD).⁷⁰⁰ Sulfur mustard (SM) intoxication leads to pulmonary complications associated with the secretion of large amounts of proinflammatory cytokines. Administration of C3 curcuminoid complex (1.5 g/day) with bioperine was found to be safe, well tolerated, and suppressed expression of inflammatory mediators by inhibiting IL-8, TNF-α, TGF-β, MCP-1, Sp, hs-CRP, and CGRP.⁷⁰¹ The same group showed that this combination was beneficial in modulating systemic inflammation by reducing serum MDA and inducing GSH in SM-induced patients having pulmonary complications.⁷⁰²

4.2.15. Turmeric and Curcumin in Skin Diseases

Turmeric is effective in the treatment of skin disorders. For instance, a topical herbal formulation containing turmeric remarkably reduced semiquantitative scores of erythema and edema in eczema. The topical application of the formulation also improved itching, scaling, and lichenification associated with eczema.⁷⁰³ The application of turmeric reduced pruritus in pregnant people and aided in healing cesarean scars.^704,705 Another study reported that a turmeric-containing polyherbal supplement alleviated facial redness compared to turmeric alone, suggesting the role of turmeric in treating skin conditions.⁷⁰⁶ A randomized, double-blind, placebo-controlled study showed that curcumin (30 mg/day) with hot water extracts of C. longa increased the water content in the skin of healthy individuals.⁷⁰⁷ Another clinical trial showed that the application of Herbavate cream twice daily for 4 weeks reduced the symptom score in patients with eczema.⁷⁰⁸ In addition, the application of tetrahydrocurcuminoid cream (a phosphatidyl liposome formulation) with targeted narrowband UVB treatment increased overall re-pigmentation in vitiligo compared to standalone UVB treatment.⁷⁰⁹ In another study, administering curcuminoids (1 g/day) with piperine for 4 weeks reduced IL-8, CGRP, hs-CRP, inflammation, and pruritus scores in patients with sulfur-mustard-induced cutaneous complications.⁷¹⁰ Further, in a randomized, double-blind clinical trial, 1 g/day of curcuminoids with bioperine remarkably reduced symptoms and disease severity in sulfur-mustard-induced pruritus.⁷¹¹

4.2.16. Turmeric and Curcumin in Stress/Oxidative Distress

Oxidative stress can be defined as a relative increase in ROS versus antioxidants and has been linked to the development of diseases such as CVDs, cancers, neurological disorders, and diabetes.⁷¹² The natural spice turmeric and its active component curcumin have shown promise in the prevention and treatment of oxidative stress. For example, the administration of 1 g and 500 mg of CurQfen in patients with occupational stress improved their QoL and decreased anxiety, fatigue, and oxidative stress by inhibiting lipid peroxidation. The dosages showed high absorption and better pharmacokinetic properties.⁷¹³ In addition, the consumption of 1 g of curcumin with piperine per day for 3 months in arsenic-induced oxidative stress was shown to induce antioxidant activity by inhibiting DNA damage, ROS generation, and lipid peroxidation.⁷¹⁴ Administration of curcumin capsules reduced ROS metabolites and enhanced biological antioxidant potential in subjects with exercise-induced oxidative stress.⁷¹⁵ In another study, a 90 mg single dose of curcumin 2 h before exercise was shown to induce antioxidant activity by suppressing oxidative stress in individuals with exercise-induced oxidative stress. In the same study, a higher curcumin dose of 90 mg given 2 h before and immediately after exercise also suppressed oxidative stress.⁷¹⁶ Further, a single-blind, randomized clinical trial of curcumin supplementation (180 mg/day) either 7 days before or 4 days after eccentric exercise showed a reduction in muscle soreness and an increased ROM in men with eccentric exercise-induced muscle damage.⁷¹⁷ Furthermore, daily supplementation with 1.5 g of curcumin (500 mg, 3× daily) for 28 days reduced muscle soreness, oxidative damage, and creatine kinase levels in patients with exercise-induced oxidative stress and inflammation (n = 20).⁷¹⁵

4.2.17. Turmeric and Curcumin for Other Diseases

Turmeric and curcumin possess tremendous potential in treating various other diseases and miscellaneous conditions.

The use of synthetic drugs is often associated with severe side effects. One of the adverse side effects of standard antituberculosis drugs (ATT) is hepatoxicity. When the ATT is administered in combination with an herbal formulation containing turmeric, the incidence of hepatotoxicity is decreased, and the levels of the critical markers ALT, AST, and bilirubin are improved. The treatment further attenuated the incidence of poorly resolved parenchymal lesions thereby improving patient compliance.⁷¹⁸ Supplementation with turmeric also reduced the consultation rate and constipation in patients with diarrhea.⁷¹⁹ In another study, a high-saturated-fat, high-carbohydrate meal with a spice blend containing turmeric reduced postprandial secretion of the inflammatory cytokine IL-1β in overweight men at risk of CVD.⁵⁰⁷ Turmeric was also shown to repair tendons and reduce associated pain in patients with tendinopathy.^720,721 A randomized, open-label clinical trial of curcumin (45 mg) intake as an oral film prior to alcohol consumption effectively reduced alcohol-induced hangover symptoms, such as dizziness, stomachache, and palpitations.⁷²² A randomized, double-blind, placebo-controlled clinical trial of curcumin demonstrated reduced pain and severity scores in patients with chronic dyspepsia (n = 132).⁷²³ As an antiseptic solution, curcumin was shown to remarkably reduce redness, edema, ecchymosis, discharge, and approximation score and enhance healing compared to povidone-iodine solution in people who underwent episiotomy (n = 120).⁷²⁴ Further, a double-blind, randomized clinical trial of curcumin cream (2%) applied for 10 days showed remarkably reduced episiotomy pain and increased wound healing.⁷²⁵ A pseudo-randomized crossover trial of escalating curcumin dose from 1 g/day to 4 g/day every 30 days showed reduced disease severity in patients with gulf war illness (n = 39) of unknown etiology.⁷²⁶ In another study, 1000 mg/day of curcumin for 8 weeks reduced serum urate in 39 patients with hyperuricemia.⁷²⁷ Moreover, curcumin 500 mg/day along with ω-3 fatty acids (1.5 g/day), rutin (500 mg/day), and whey protein isolate (20 g/day) led to enhanced knee extension strength and gait speed in 41 elderly patients with sarcopenia.⁷²⁸ An open-label, controlled clinical trial showed that administration of Killox (curcuminoids 190 mg, resveratrol 20 mg, N-acetyl cysteine 100 mg, and zinc 6 mg) reduced postoperative and late complications and duration of irritation in patients with transurethral resection of the bladder (n = 10), transurethral resection of the prostate (n = 40), and benign prostate hyperplasia (n = 30).⁷²⁹ This study also showed that the formulation is safe and did not cause any adverse side effects, nor did it alter the efficacy of other treatments.⁷²⁹ In women with self-perceived hair thinning, administration of 4 capsules of Neutrafol containing natural compounds such as ashwagandha, capsaicin, curcumin, HA, marine collagen, piperine, saw palmetto, and a tocotrienol-rich tocotrienol/tocopherol complex showed an increase in the number of terminal and vellus hairs, hair growth, quality, thickness, and volume.⁷³⁰ Another study aimed to determine the effect of curcumin on hormones and oxidative status in 56 infertile men treated with 80 mg/day of curcumin nanomicelles for 10 weeks. The results showed that the treatment enhanced total sperm count and total antioxidant capacity.⁷³¹

In cancer patients, the administration of 500 mg Meriva thrice daily exhibited a protective effect against chemotherapy- and radiotherapy-induced side effects by reducing the burden associated with these treatments.⁷³² Theracurmin was investigated for its efficacy in reducing muscle damage. In 14 patients, daily administration of 300 mg Theracurmin for 4 weeks ameliorated muscle damage by inducing faster maximal voluntary contraction torque of elbow flexors and blocking CK activity.⁷³³ Supplementation with 5 g of curcumin was also effective in improving muscle performance in individuals suffering from inflammation-related muscle damage and soreness and was found to modulate IL-6 and CK activities.⁷³⁴ However, in another study, 100 mg/day of curcumin had no effect on COX-2 and IL-10 levels in women with preeclampsia.⁷³⁵

Thus, various studies have defined the potential of turmeric, curcumin, and their formulations in the management of several diseases, proving them to be effective agents.

5. Conclusion

Extensive investigations over the past half-century has revealed that turmeric and its active component offers potential therapeutic benefits in multiple chronic disease conditions. Several clinical studies have examined the efficacy of curcumin in treating cancer, cardiovascular ailments, diabetes, obesity, metabolic syndromes, and neurological disorders. The impact of curcumin on chronic illnesses seems promising based on the data from completed clinical trials. Turmeric and curcumin alleviate symptoms of illness, modulate biomarker levels, improve QoL, and slow the progression and resurgence of disease in persons with diverse health conditions. The efficacy of these remarkable compounds in adjuvant treatment demonstrated remarkable potential in several clinical and preclinical trials. In addition, it sensitizes cancerous cells to radiation and chemotherapy. Being a hydrophobic compound, curcumin is less bioavailable than desired. However, a number of formulations have been developed to increase its bioavailability, and numerous clinical trials have demonstrated the enhanced bioavailability of these curcumin formulations in humans. More comprehensive, well-controlled clinical trials are now needed for a complete evaluation of the potential of turmeric and curcumin in terms of optimal dosing, mode of administration, and disease targets, as well as possible interactions with other medications. After all, the natural analogs derived from turmeric and curcumin metabolites, as well as naturally occurring and manufactured analogs, exhibit intricate structural differences. A study of this huge array of compounds and related pharmacodynamic studies will allow us to standardize the design of a molecule imitating the scaffold curcumin and replicating its bioactivities. However, the precise significance of various functions of curcumin in determining its unique physicochemical characteristics and pleiotropic effects in both natural and manufactured curcuminoids remains unknown. Hence, further investigations involving structure–activity relationships would undoubtedly offer a stable platform for elucidating the vast range of biological activities of this golden spice. Overall, turmeric and curcumin’s positive effects on human health and illness prevention will be better understood as a consequence of continuing clinical investigations, strengthening their prospective usage as a supplement to standard medication.

The authors declare no competing financial interest.