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Nutrition Science

Turmeric

Potential Health Benefits

Singletary, Keith PhD

Author Information
doi: 10.1097/NT.0000000000000392

Abstract

The spice turmeric is a botanical that is used widely in the Middle East and Asia, not only to impart a distinctive flavor to foods, but also purportedly to provide health benefits as a component of traditional medicines. Recently, it has been added to nutraceuticals, beverages, and processed foods. Turmeric is obtained from the rhizome of Curcuma longa L. (Zingiberaceae family) (Figure 1). Three curcuminoids, curcumin, demethoxycurcumin, and bisdemethoxycurcumin (Figure 2), of which curcumin is the most prevalent, are among many bioactive ingredients in turmeric. The yellow pigment curcumin or diferuloylmethane makes up 60% to 70% of crude turmeric extracts and is the principal curcuminoid evaluated for health-promoting activities.1 In addition, turmeric contains sugars, proteins, resins, and volatile oils, such as turmerone, atlantone, and zingiberene, some of which may have bioactivity as well.1–4 Numerous preclinical investigations identified a variety of potential health benefits, including treatment for heart disease, arthritis, Alzheimer's disease, gastrointestinal disorders, and the metabolic syndrome (MetS).5 Initial human trials examining the biological actions of oral curcumin given as raw turmeric powder (Figure 3) were confronted with its poor water solubility, low intestinal absorption, and rapid metabolic degradation, which limited its systemic distribution and bioavailability.1 Consumption of gram quantities of curcumin powder by human subjects was needed to obtain measurable amounts of circulating curcumin from which discernable biological actions were inconsistently observed.1,6–10 Over the previous decade, considerable research led to improvements in curcumin's bioavailability, which has contributed to the appearance of numerous clinical studies evaluating various possible health benefits of both turmeric and curcuminoids using these new delivery approaches. Such methods include inclusion of piperine, a phytochemical that enhances intestinal uptake of curcumin, and use of novel delivery systems that complex curcuminoids within diverse matrices. For example, curcumin can be incorporated into micelles, microemulsions, liposomes, nanoparticles, and in other lipid and biopolymer particles.11–13 Curcuminoids encapsulated with turmeric essential oils, particularly with turmerone, which enhances intestinal permeability, also have been prepared. Noticeable improvements in oral bioavailability in human subjects were reported using these novel formulations,14–22 and comparative efficacies have been reported for some strategies.23–27 This narrative review examines human investigations into the effects of turmeric and its extracts and novel formulations on subjects with signs and symptoms of arthritis, type 2 diabetes mellitus (T2DM) and MetS. It may provide new insights into emerging potential health benefits of turmeric from the recent and growing number of human studies.

FIGURE 1
FIGURE 1:
Turmeric root.
FIGURE 2
FIGURE 2:
Structures of curcuminoids in turmeric.
FIGURE 3
FIGURE 3:
Turmeric ground powder.

METHODS

A search of the PubMed, ClinicalTrials.gov, and Biomed Central databases identified more than 150 preclinical and clinical reports published prior to 2019 that examined the impact of turmeric or its constituents on the biochemical and physiological characteristics of MetS, T2DM, and arthritis and on the prevention or treatment of these conditions. Search terms included C. longa L., curcumin, curcuminoids, turmeric, and diferuloylmethane. Full reports of English-language publications and English-language abstracts of foreign-language articles from peer-reviewed journals were the primary sources of information. The human studies identified were inconsistent in methodological rigor and differed, for example, in inclusion of appropriate controls, extent of blinding, completeness of participant descriptions, randomization, procedures for statistical analysis of data, and chemical characterization of intervention treatments. Nonetheless, all published English-language human investigations identified were included in this narrative review so that the totality and diversity of information can be evaluated, and issues for future research can be identified. Additional information was gleaned from bibliographies within these sources. Studies examining curcumin within multi-ingredient preparations were not included in this review.

Potential Health Benefits

The composition of turmeric or curcumin samples used in published human studies routinely is not well characterized. These “curcumin” products likely are curcuminoid mixtures that consist of varying amounts not only of curcumin but also of demethoxycurcumin and bisdemethoxycurcumin in the turmeric extracts. Therefore, unless a trial specifically identifies a treatment sample as isolated diferuloylmethane, the terms curcuminoids (C) or C-fraction will be used in tables and text in the place of the term curcumin. Also, in this regard, chemical analyses of curcuminoid content in samples will be included in supplementary tables if reported in an article.

Arthritis

Details of 21 clinical trials assessing the effectiveness of turmeric powder or curcuminoid-containing supplements on signs and symptoms of arthritis are included in Supplemental Digital Content 1, http://links.lww.com/NT/A27. A summary of these studies is presented in Table 1. Most of these trials evaluated patients with knee osteoarthritis, and the patients enrolled were predominantly females (75%). Patient populations were derived primarily from the Middle East and Asia. The trials measured both intensity of pain and improvements in physical functioning using several indices. The Western Ontario and McMaster Universities Osteoarthritis Index, the Lequesne's Pain Functional Index, and the Japanese Knee Osteoarthritis Measure evaluate improvements in pain and functionality, whereas the visual analog scale measures severity of pain. The Disease Activity Score measures the number of swollen and tender joints; blood markers of inflammation, such as erythrocyte sedimentation rate and C-reactive protein (CRP); and the patient's global assessment of health. The American College of Rheumatology survey measures similar criteria as the Disease Activity Score. The Clinician Global Impression of Change measures joint tenderness, crepitus, alignment, movement, and muscle wasting.

TABLE 1
TABLE 1:
Summary of Clinical Trials Evaluating Curcuma longa for Arthritis

The curcuminoids were administered orally in various formulations. Six trials evaluated the efficacy of simple curcuminoid formulations,28–33 which essentially were turmeric powder or dried organic solvent (usually ethanol) extractions from this powder that may or may not have had the volatile oil portion removed. These samples contained varying ratios of curcuminoids and were administered at doses of 90 mg/d to 1.2 g/d for periods of 2 weeks to 4 months. When compared with baseline values, significant improvements in arthritic symptoms, such as stiffness, walking pain, or Western Ontario and McMaster Universities Osteoarthritis Index scores, were recorded for those receiving curcuminoids alone.28,29,32 In comparisons of efficacy between curcuminoids and positive controls (nonsteroidal anti-inflammatory drugs [NSAIDs]), the potency of NSAID treatment was not superior to (not significantly different than) that of the curcuminoid preparations.

More than a dozen arthritis trials were performed using a variety of proprietary curcuminoid preparations engineered to improve oral bioavailability. All studies demonstrated some improvement in patients' arthritis symptoms, although changes in specific clinical measures varied among trials. Taken together, the trials that provided statistical comparisons of curcuminoid outcomes with those of placebo controls34,38,42,43,45,47,48 reported significant improvement in either pain or physical function. For those trials evaluating curcuminoid formulations in comparison to an NSAID control group, comparable efficacy was observed. When curcuminoids were provided as adjuvants with diclofenac (a nonsteroidal anti-inflammatory agent) dosing, patient improvement was not consistently observed, compared with those treated with diclofenac alone.30,33,41,44 Patients treated with curcuminoids in several trials34,38,45,47 reported decreased use of rescue pain medications. It is noteworthy that a curcuminoid-free polysaccharide fraction isolated from turmeric (Turmacin) significantly decreased arthritis symptom scores, compared with placebo.47 Polysaccharides from C longa have been reported to have anti-inflammatory and immunomodulatory activities, as have sesquiterpenoids in water extracts.49–51 Systematic reviews of arthritis trials indicate that minor adverse gastrointestinal disturbances were the most common adverse effects of turmeric and curcuminoid administration, although curcuminoids generally exhibited a lower risk of these events compared with prescribed drugs.52,53

To obtain insights into possible mechanisms of action, blood levels of CRP and inflammation-associated cytokines were measured in 7 trials,35–39,42,43 but no consistent pattern of change was observed. One study31 examined knee joint aspirations from patients and found that, when compared with baseline values, the administration of either curcuminoids or diclofenac resulted in similar, not significantly different, suppression of cyclooxygenase-2 secretion by synovial fluid monocytes. In this study, no data were provided for changes in physical symptoms; thus, determining if these changes in a biomarker for joint inflammation actually translated to relief of arthritic symptoms was not possible. This is important because the dose of curcuminoids (90 mg/d) given in this trial was low, compared with other trials.

Systematic reviews and meta-analyses of select arthritis trials provide evidence that supports the efficacy of curcuminoids in treating arthritis with fewer adverse effects than with NSAIDs.35,43,52–58 However, a variety of trial limitations and shortcomings noted in these systematic reviews make recommendations for clinical use difficult to provide. The relatively small number of carefully performed randomized controlled trials (RCTs) is a significant limitation. The designs and methodological qualities of the trials varied considerably. Most often statistical analyses of treatment responses were performed by evaluating within-group differences between baseline and posttreatment values rather than between treatment and control or placebo groups. Some trials lacked controls altogether. Moreover, patient populations were small, the durations of treatments were short, long-term follow-up was lacking (eg, frequency of arthritic flare-ups and remissions), and baseline symptoms of patients among trials varied in severity. Chemical analyses of the formulations and extracts were not consistently provided. Nonetheless, collectively, these meta-analyses suggest that there is potential for curcuminoids to improve the quality of life of arthritis patients. Additional large, well-controlled trials are clearly warranted.

MetS and T2DM

In Supplemental Digital Content 2, http://links.lww.com/NT/A28, the details of 62 clinical trials that evaluated the effects of turmeric powder or curcuminoid extracts on glucose and insulin regulation and serum lipid profiles are listed. Prior to 2009, only 6 trials were identified. Today, novel delivery systems increase the bioavailability of curcumin. Because of this, in the last 10 years, more than 50 reports have been published of trials investigating the impact of different forms and doses of oral turmeric and curcuminoids in healthy adults, as well as in those with T2DM and those with MetS. These trials are summarized in Table 2. Human studies evaluating similar endpoints in subjects with nonalcoholic fatty liver disease (NAFLD) are included in Supplemental Digital Content 3, http://links.lww.com/NT/A29.

TABLE 2
TABLE 2:
Summary of Clinical Trials Evaluating Effects of Curcuma longa on Glucose/Insulin Regulation and Serum Lipid Profiles

In healthy adults, 6 studies evaluated curcuminoids at doses as high as 6 g/d for periods as long as 6 months.59–64 Outcomes were inconsistent for measurements of blood glucose levels and lipid profiles. Similar disparate effects were observed in healthy adults when curcuminoids were provided in bioavailability-enhanced forms such as in solid lipid particles or as a phosphatidylcholine-phytosome complex.65–67

In obese individuals, findings from 10 reports68–77 show no consistent influence of curcuminoid treatment on oxidative stress biomarkers, serum levels of cytokines, growth factors, and hormones, or on blood pressure and blood glucose and lipid concentrations, compared with controls. Dose and form of curcuminoids as well as age and gender of subjects varied considerably among trials.

For those trials investigating subjects with prediabetes or hypercholesterolemia,19,78–82 the limited number of studies precludes making generalities about the effectiveness of different turmeric or curcuminoid forms. However, of note, an alcohol extract of turmeric (1.5 g/d) given to prediabetic individuals for 9 months78 significantly decreased fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and insulin resistance (IR), compared with controls. It also reduced the prevalence of newly diagnosed T2DM patients. This is one of the longest trials evaluating a health benefit of curcuminoids and underscores the importance of the long-term examination of this phytochemical's actions, especially if early stages in the progression to disease are evaluated. Also, when turmeric powder was given as a tea preparation in 1 trial,79 improvements in blood lipid profile were observed, compared with controls, suggesting that curcuminoid administration as a beverage may be worthwhile to more routinely examine.

In 20 investigations, a variety of curcuminoid preparations were administered to subjects with T2DM.83–102 For those trials evaluating raw turmeric powder or curcuminoid fractions, no consistent effects were noted for measures of FBG, HbA1c, lipid profiles, antioxidant status, and IR. Doses administered were from 66 mg/d to 1.3 g/d for periods of 4 weeks to 6 months. Determination of doses was problematic, because some studies did not provide curcuminoid content within the powder or extracted samples. Two studies examined curcuminoids as an adjunct to drugs for treating hyperglycemia. In combination with metformin, curcuminoids decreased blood low-density lipoprotein (LDL) levels and had no effect on FBG, postprandial blood glucose, HbA1c, and IR, compared with those given metformin alone.91 In combination with the sulfonylurea glyburide, curcuminoid administration resulted in significant improvements in postprandial blood glucose and blood lipids, compared with glyburide alone, and also increased the total area under the first moment of the concentration-time curve for glyburide.90 Use of curcuminoids as an adjunct to these types of drugs deserves more scrutiny, as does determining whether curcuminoids also can affect drug bioavailability. Of interest, 3 investigations84,86,98 observed beneficial effects of these proprietary curcuminoid formulations on diabetic pathologies. This included decreases in foot microangiopathy, foot edema, and retinal edema, as well as in functional impairments. Microcirculation, visual acuity and blood flow improved. In light of these findings, future studies should document changes in diabetic pathologies.

The influence of curcuminoids on MetS was described in 14 reports.103–116 For those studies of MetS in which powdered turmeric or curcuminoid fractions were evaluated, no consistent improvements in blood lipid and glucose levels or in insulin sensitivity were observed.104,105,115,116 Of note, 1 trial measured liver morphology and detected a lower level of liver steatosis after 12 months of curcuminoid dosing,101 compared with baseline. For those 13 MetS trials administering bioavailability-enhanced preparations, no consistent changes were observed in blood glucose and lipid levels, as well as for body mass index and biomarkers of antioxidant status, compared with controls.

For subjects with NAFLD, 5 different trials were identified in which 4 different turmeric preparations were separately evaluated (Supplemental Digital Content 3, http://links.lww.com/NT/A29). Compared with subjects administered placebo, NAFLD patients administered curcuminoids showed significant improvements in FBG for 3 of 4 trials, in HbA1c for 2 of 3 trials, and in IR for 2 of 3 trials.118–122 For 3 of 4 studies, serum total cholesterol (TC), triglycerides (TGs), and LDL significantly decreased, compared with placebo. No benefits of curcuminoid dosing on serum alanine aminotransferase and aspartate aminotransferase concentrations were observed. In a recent RCT, NAFLD patients were given 250 mg of a phospholipid form of curcuminoids for 8 weeks while examining changes in nuclear magnetic resonance spectroscopy (NMR)-based serum metabolic profiles. Compared with placebo, curcuminoid treatment variously altered levels of specific amino acids, tricarboxylic acid cycle intermediates, bile acids, and gut microbiota.123 This may be a complementary approach to use in understanding the mechanisms of action of curcuminoids in this disorder.

Two trials of subjects with coronary artery disease showed no benefit of curcuminoid administration on serum lipid profiles or on blood glucose levels.124,125

Recent systematic reviews and meta-analyses of select trials (that were judged to be of sufficient quality for analysis) shown in Table 2 reached different conclusions regarding the efficacy of curcuminoids for T2DM and MetS. Based on the meta-analysis of Azhdari et al126 of MetS RCTs,104–107,116,127 curcuminoid intake was associated with improvements in FBG, TG, and high-density lipoprotein (HDL) levels and diastolic blood pressure. Another meta-analysis128 of prediabetes and T2DM trials, which were typically of 2- to 3-month duration,78,83,85,88,89,92,93,129 found that curcuminoids significantly decreased HbA1c levels in prediabetes and T2DM and decreased FBG levels in T2DM, but no significant improvement in lipid profiles was observed. It is worth noting that in this meta-analysis these authors conducted a separate sensitivity analysis to assess the statistical robustness of their findings. To do so, they removed a larger T2DM trial of longer duration (>3 months) from the analysis and found that the beneficial effects on glycemic outcomes in T2DM were no longer evident. Based on this assessment, the authors suggested that curcuminoid administration for shorter periods (2- to 3-month duration) might not be adequate to detect improvements in glycemic control in T2DM.

A meta-analysis of 7 trials130 with patients demonstrating cardiovascular risk factors determined that turmeric and curcuminoids significantly decreased blood LDL and TG levels, but did not improve HDL or TC levels. This meta-analysis was not in agreement with the prior meta-analysis by Sahebkar,131 which found no significant effect of curcuminoid dosing on any of the blood lipid parameters measured. Another meta-analysis of 26 RCTs of patients with MetS and related disorders132 determined that curcuminoid administration was associated with significant decreases in FBG, IR, HbA1c, TG, and TC, but not in LDL and HDL levels.

Several factors likely contributed to inconsistencies in outcomes among the trials shown in Table 2, as well as in the conclusions from systematic reviews and meta-analyses. Rigor of statistical analyses of data varied considerably among RCTs. In some studies, outcomes measured in treatment and placebo groups at the conclusion of interventions were compared with baseline values within groups. In contrast, other trials statistically analyzed treatment group outcomes with those of appropriate controls. Trial populations were generally small and frequently from South East Asia, India, Iran, and Pakistan. Moreover, there was substantial heterogeneity among studies in participants' baseline characteristics, stage of disease at enrollment, gender, comorbidities, comedications (often not reported), trial duration, doses administered, characteristics of curcuminoid formulations, and subjects' diets and lifestyles.126,128,130,132 It may be of value to analyze treatment effectiveness based on gender, because 2 trials detected different male versus female responses for blood ghrelin103 and HbA1c levels.107

Mechanisms of Action

The mechanisms of action of curcumin in humans are not well understood. Inflammatory cytokines and biochemical markers of oxidative status were measured in some arthritis trials, and there is preliminary evidence from meta-analyses that curcuminoids may decrease biomarkers of systematic inflammation and increase serum adiponectin levels.133–136 For trials of T2DM and MetS, there is preliminary evidence from meta-analyses that curcuminoids may reduce serum levels of CRP and leptin.137,138

Preclinical experiments indicate that changes in cellular inflammatory responses, oxidative stress, chondrocyte destruction and renewal, and in osteoclastogenesis contribute to the antiarthritic action of curcuminoids.139,140 Preclinical studies of glucose and lipid homeostasis indicate that curcuminoids can modulate insulin action, lipolysis, adipogenesis, lipoprotein function, and nutrient absorption.126,132,136,141–143

Safety

Turmeric, its essential oils, and oleoresins are generally recognized as safe by the US Food and Drug Administration. A similar designation for curcuminoids has not yet been published by the Food and Drug Administration. Studies in animals indicate that curcuminoids have relatively low potential for toxicity.54,144–146 In humans, the intake of turmeric powder as high as 8 g/d has apparently been tolerated with only minor adverse consequences, mainly gastrointestinal distress.147 However, safe doses of more bioavailable formulations have not been established and possibly may be different and substantially less. Thus, more careful documentation in human trials of adverse effects of these novel curcuminoid delivery methods needs to be compiled. In this regard, it has been cautioned that a new bioavailable form of curcuminoid might “narrow its therapeutic window and lead to off-target toxicity.”1 Additionally, the impact of curcuminoid dose on bioavailability and bioactivity of other ingested dietary components has received little attention. For example, data on curcuminoid intake and mineral absorption are conflicting.148,149 There also needs to be an examination of potential drug interactions following curcuminoid administration, because both inhibitory and enhancing effects on drug efficacy in humans have been reported.2,150–157 As with any herbal supplement, an awareness of reports of adverse consumer responses is important. Recently, Belgium's Federal Agency for Food Chain Safety and Italy's National Institute of Health warned consumers to avoid specific turmeric-containing supplements associated with an outbreak of acute cholestatic hepatitis (https://www.nutraingredients.com/Article/2019/07/11/Belgium-recall-same-curcumin-based-supplement-linked-to-Italian-hepatitis-cases?utm_source=newsletter_daily#).

Future Studies

Research findings on curcuminoids for the treatment of arthritis and possibly of T2DM are promising. A number of issues can be addressed in future investigations to improve their quality, reproducibility, and usefulness for crafting recommendations regarding curcuminoid's potential health benefits. Larger and longer-duration, high-quality RCTs are needed that study different population ages, gender and ethnic representation, baseline disease severity, and adverse effects and that use multiple dosing levels of chemically defined samples. As indicated previously, the bioavailability of curcuminoids from raw turmeric is exceptionally low, and the actual content of curcuminoids within the treatment sample, generally considered to be approximately 3%, is often not reported. The new delivery forms of curcuminoids may improve relief of disease symptoms compared with poorly absorbed raw turmeric and its simple, solvent extracts and thus deserve closer scrutiny.130,131 Although different forms of bioavailable curcuminoids were administered in trials, no supportive data were provided substantiating that absorption and distribution necessarily improved in these patient populations. This is important because high interindividual variability in pharmacokinetics and nonlinear dose dependency were observed for one trial of a novel formulation.158 Serum or urine levels of curcuminoids and/or their metabolites need to be measured in trials so as to assess relative bioavailability and compliance along with efficacy.54,159 In addition, the influence of comedications on curcuminoid efficacy should be clarified. The potential of curcuminoids when used in combination with NSAIDs and hypoglycemic drugs to improve efficacy, reduce doses needed, and lower adverse effects of drugs warrants more thorough characterization.

CONCLUSION

In light of the evidence that the small amounts of curcuminoids in turmeric powder are very poorly bioavailable, culinary quantities of turmeric powder added to foods for sensory purposes are unlikely to provide meaningful health benefits for the conditions reviewed. Based on current, preliminary evidence from human trials, curcuminoid extracts and other novel formulations may have potential to help manage symptoms of T2DM, MetS, and especially arthritis. Yet, due to inconsistent findings from trials that differ substantially in quality, and due to incomplete understanding of curcuminoids' effective doses and duration and of their safety and their interactions with comedications, it is premature to recommend their supplemental use to improve health in a clinical setting or in the general population. Future larger, longer, high-quality RCTs are needed to better characterize any potential health benefits of this spice's bioactive constituents.

REFERENCES

1. Nelson K, Dahlin J, Bisson J, et al. The essential medicinal chemistry of curcumin. J Med Chem. 2017;60:1620–1637.
2. Eke-Okoro U, Raffa R, Pergolizzi J, et al. Curcumin in turmeric: basic and clinical evidence for a potential role in analgesia. J Clin Pharm Ther. 2018;43:460–466.
3. Aggarwal B, Yuan W, Li S, Gupta S. Curcumin-free turmeric exhibits anti-inflammatory and anticancer activities: identification of novel components of turmeric. Mol Nutr Food Res. 2013;57:1529–1542.
4. Kawasaki K, Okuda-Hanafusa C, Aoyagi M, et al. Inhibitory effect of the compounds from the water extract of Curcuma longa pn the production of PGE2 and NO in a macrophage cell line stimulated by LPS. Biosci Biotechnol Biochem. 2018;82:2109–2117.
5. Singletary K. Turmeric: an overview of potential health benefits. Nutr Today. 2010;45:216–225.
6. Vareed S, Kakarala M, Ruffin M, et al. Pharmacokinetics of curcumin conjugate metabolites in healthy human subjects. Cancer Epidemiol Biomarkers Prev. 2008;17:1411–1417.
7. Klickovic U, Doberer D, Gouya G, et al. Human pharmacokinetics of high dose oral curcumin and its effect on heme oxygenase-1 expression in healthy human subjects. Biomed Res Intern. 2014;2014:458592. doi.org/10,1155/2014/458592.
8. Garcea G, Berry D, Jones D, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev. 2005;14(1):120–125.
9. Garcea G, Jones D, Singh R, et al. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br J Cancer. 2004;90:1011–1015.
10. Lao C, Ruffin MT 4th, Normolle D, et al. Dose escalation of curcuminoid formulation. BMC Complement Altern Med. 2006;6:10–13.
11. Sanidad K, Sukamtoh E, Xiao H, McClements DJ, Zhang G. Curcumin: recent advances in the development of strategies to improve oral bioavailability. Ann Rev Food Sci Technol. 2019;10:597–617.
12. Douglass B, Clouatre D. Beyond yellow curry: assessing commercial curcumin absorption technologies. J Am Coll Nutr. 2015;34:347–358.
13. Prasad S, Tyagi A, Aggarwal B. Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from golden spice. Cancer Res Treat. 2014;46:2–18.
14. Shoba G, Joy D, Joseph T, et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64:353–356.
15. Schiborr C, Kocher A, Behnam D, et al. The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes. Mol Nutr Food Res. 2014;58:516–527.
16. Briskey D, Sax A, Mallard A, Rao A. Increased bioavailability of curcumin using a novel dispersion technology system (LipiSperse®). Eur J Nutr. 2019;58:2087–2097. doi.org/10.1007/s00394-018-1766-2.
17. Sasaki H, Sunagawa Y, Takahashi K, et al. Innovative preparation of curcumin for improved oral bioavailability. Biol Pharm Bull. 2011;34:660–665.
18. Vitaglione P, Lumaga R, Ferracane R, et al. Curcumin bioavailability from enriched bread: the effect of microencapsulated ingredients. J Agric Food Chem. 2012;60:3357–3366.
19. Kocher A, Bohnert L, Schiborr C, Frank J. Highly bioavailable micellar curcuminoids accumulate in blood, are safe and do not reduce blood lipids and inflammation markers in moderately hyperlipidemic individuals. Mol Nutr Food Res. 2016;60:1555–1563.
20. Antony B, Merina B, Iyer V, et al. A pilot cross-over study to evaluate human oral bioavailability of BCM-95®CG (Biocurcumax™), a novel bioenhanced preparation of curcumin. Ind J Pharm Sci. 2008;70:445–449.
21. Morimoto T, Sunagawa Y, Katanasaka S, et al. Drinkable preparation of Theracurmin exhibits high absorption efficiency—a single-dose, double-blind, 4-way crossover study. Biol Pharm Bull. 2013;36:1708–1714.
22. Mahale J, Singh R, Howells L, et al. Detection of plasma curcuminoids from dietary intake of turmeric-containing food in human volunteers. Mol Nutr Food Res. 2018;62. doi:.
23. Asher G, Xie Y, Moaddel R, et al. Randomized pharmacokinetic cross-over study comparing two curcumin preparations in plasma and rectal tissue of healthy human volunteers. J Clin Pharmacol. 2017;57:185–193.
24. Purpura M, Lowery R, Wilson J, et al. Analysis of different innovative formulations of curcumin for improved relative oral bioavailability in human subjects. Eur J Nutr. 2018;57:929–938.
25. Gopi S, Jacob J, Varma K, et al. Comparative oral absorption of curcumin in a natural turmeric matrix with two other curcumin formulations: an open-label parallel-arm study. Phytother Res. 2017;31:1883–1891.
26. Jäger R, Lowery R, Calvanese A, et al. Comparative absorption of curcumin formulations. Nutr J. 2014;13:11–18.
27. Sunagawa Y, Hirano S, Katanasaka Y, et al. Colloidal submicron-particle curcumin exhibits high absorption efficiency-a double-blind, 3-way crossover study. J Nutr Sci Vitaminol. 2015;61:37–44.
28. Deodhar S, Sethi R, Srimal R. Preliminary study on anti-rheumatic activity of curcumin (diferuloyl methane). Ind J Med Res. 1980;71:632–634.
29. Kuptniratsaikul V, Thanakhumtorn S, Chinswangwatanakul P, et al. Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. J Altern Complement Med. 2009;15:891–897.
30. Pinsornsak P, Niempoog S. The efficacy of Curcuma longa L. extract as an adjuvant therapy in primary knee osteoarthritis: a randomized control study. J Med Assoc Thai. 2012;95(suppl 1):S51–S58.
31. Kertia N, Asdie A, Rochmah W. Marsetyawan. Ability of curcuminoid compared to diclofenac sodium in reducing the secretion of cyclooxygenase-2 enzyme by synovial fluid's monocytes of patients with osteoarthritis. Indones J Intern Med. 2012;44:105–113.
32. Kuptniratsaikul V, Dajpratham P, Taechaarpornkul W, et al. Efficacy and safety of Curcuma domestica extracts compared to ibuprofen in patients with knee osteoarthritis: a multicenter study. Clin Invest Aging. 2014;9:451–458.
33. Srivastava S, Saksena AK, Khattri S, Kumar S, Dagur RS. Curcuma longa extract reduces inflammatory and oxidative stress biomarkers in osteoarthritis of knee: a four-month, double-blind, randomized, placebo-controlled trial. Inflammopharmacology. 2016;24:377–388.
34. Panahi Y, Rahimnia A, Sharafi M, et al. Curcuminoid treatment for knee osteoarthritis: a randomized double-blind placebo-controlled trial. Phytother Res. 2014;28:1625–1631.
35. Rahimnia A, Panahi Y, Alishiri G, et al. Impact of supplementation with curcuminoids on systemic inflammation in patients with knee osteoarthritis: findings from a randomized double-blind placebo-controlled trial. Drug Res (Stuttg). 2015;65:521–525.
36. Panahi Y, Alishiri G, Parvin S, Sahebkar A. Mitigation of oxidative stress by curcuminoids in osteoarthritis: results of a randomized controlled trial. J Diet Suppl. 2016;13:209–220.
37. Belcaro G, Cesarone M, Pellegrini L, et al. Product-evaluation registry of Meriva®, a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis. Panminerva Med. 2010;52:S55–S62.
38. Belcaro G, Cesarone MR, Dugall M, et al. Efficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients. Altern Med Rev. 2010;15:337–344.
39. Henrotin Y, Gharbi M, Dierckxsens Y, et al. Decrease of a specific biomarker of collagen degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an exploratory clinical trial. Complement Altern Med. 2014;14:159–165.
40. Appelboom T, Maes N, Albert A. A new Curcuma extract (Flexyfytol®) in osteoarthritis: results from a Belgian real-life experience. Open Rheumatol J. 2014;8:77–86.
    41. Chandran B, Goel A. A randomized, pilot study to assess efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012;26:1719–1725.
    42. Amalraj A, Varma K, Jacob J, et al. A novel highly bioavailable curcumin formulation improves symptoms and diagnostic indicators in rheumatoid arthritis patients: a randomized, double-blind, placebo-controlled, two-dose, three-arm, and parallel-group study. J Med Food. 2017;20:1022–1030.
    43. Haroyan A, Mukuchyan V, Mkrtchyan N, et al. Efficacy and safety of curcumin and its combination with boswellic acid in osteoarthritis: a comparative, randomized, double-blind, placebo-controlled study. BMC Complement Altern Med. 2018;18:7–22.
    44. Shep D, Khanwelkar C, Gade P, Karad S. Safety and efficacy of curcumin versus diclofenac in knee osteoarthritis: a randomized open-label parallel-arm study. Trials. 2019;20:214–224.
    45. Nakagawa Y, Mukai S, Yamada S, et al. Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. J Orthop Sci. 2014. doi:.
    46. Shin Y, Suk M, Jang H, Choi H. Short-term effects of Theracurmin dose and exercise type on pain, walking ability, and muscle function in patients with knee osteoarthritis. J Exer Rehab. 2017;13:684–692.
      47. Madhu K, Chanda K, Saji M. Safety and efficacy of Curcuma longa extract in the treatment of painful knee osteoarthritis: a randomized placebo-controlled trial. Inflammopharmacology. 2013;21:129–136.
      48. Panda S, Nirvanashetty S, Parachur V, Mohanty N, Swain T. A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of Curene® versus placebo in reducing symptoms of knee OA. Biomed Res Inter. 2018;2018:5291945. https://doi.org/10.1155/2018/5291945, 2018, 1, 8.
      49. Illuri R, Bethapudi B, Anandakumar S, et al. Anti-inflammatory activity of polysaccharide fraction of Curcuma longa extract (NR-INF-02). Antiinflamm Antiallergy Agents Med Chem. 2015;14:53–62.
      50. Pan M, Wu J, Ho C, Badmaev V. Effects of water extract of Curcuma longa (L.) roots on immunity and telomerase function. J Complement Integr Med. 2017;14, 14. doi:10.1515/jcim-2015-0107.
      51. Kawasaki K, Okuda-Hanafusa C, Aoyagi M, et al. Inhibitory effect of the compounds from the water extract of Curcuma longa on the production of PGE2 and NO in a macrophage cell line stimulated by LPS. Biosci Biotech Biochem. 2018;82:2109–2117. doi:.
      52. Gaffey A, Slater H, Porritt K, Campbell J. The effects of curcuminoids on musculoskeletal pain: a systematic review. JBI Database System Rev Implement Rep. 2017;15:486–516.
      53. Bannuru R, Osani M, Al-Eid F, Wang C. Efficacy of curcumin and Boswellia for knee osteoarthritis: systematic review and meta-analysis. Semin Arthritis Rheum. 2018;48:416–429. doi.org/10.1016/j.semarthrit.2018.03.001.
      54. Sahebkar A, Henrotin Y. Analgesic efficacy and safety of curcuminoids in clinical practice: a systematic review and meta-analysis of randomized controlled trials. Pain Med. 2016;17:1192–1202.
      55. Onakpoya I, Spencer E, Perera R, Heneghan C. Effectiveness of curcuminoids in the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomized clinical trials. Int J Rheum Dis. 2017;20:420–433.
      56. Liu X, Machado G, Eyles J, Ravi V, Hunter D. Dietary supplements for treating osteoarthritis: a systematic review and meta-analysis. Br J Sports Med. 2018;52:167–175.
      57. Daily J, Yang M, Park S. Efficacy of turmeric extracts and curcumin for alleviating the symptoms of joint arthritis: a systematic review and meta-analysis of randomized trials. J Med Food. 2016;19:717–729.
      58. Wu J, Lu M, Zhou Y. Efficacy and side effect of curcumin for the treatment of osteoarthritis: a meta-analysis of randomized control trials. Pak J Pharm Sci. 2019;32:43–51.
      59. Soni K, Kuttan R. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Ind J Physiol Pharmacol. 1992;36:273–275.
      60. Ramirez-Bosca A, Soler A, Carrion M, et al. An hydroalcoholic extract of Curcuma longa lowers apoB/apoA ratio: implications for atherogenesis prevention. Mech Age Dev. 2000;119:41–47.
      61. Baum L, Cheung S, Mok V, et al. Curcumin effects on blood lipid profile in a 6-month study. Pharmacol Res. 2007;56:509–514.
      62. Tang M, Larson-Meyer D, Liebman M. Effect of cinnamon and turmeric on urinary oxalate excretion, plasma lipids, and plasma glucose in healthy subjects. Am J Clin Nutr. 2008;87:1262–1267.
      63. Wickenberg J, Ingemansson S, Hlebowicz J. Effects of Curcuma longa (turmeric) on postprandial plasma glucose and insulin in healthy subjects. Nutr J. 2010;9:43–48.
      64. Pungcharoenkul K, Thongnopnua P. Effect of different curcuminoid supplement dosages on total in vivo antioxidant capacity and cholesterol levels of healthy human subjects. Phytother Res. 2011;25:1721–1726.
      65. DiSilvestro R, Joseph E, Zhao S, Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutr J. 2012;11:79–86.
      66. Santos-Parker J, Strahler T, Bassett C, et al. Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress. Aging. 2017;9:187–205.
      67. Thota R, Dias C, Abbott K, Acharya S, Garg M. Curcumin alleviates postprandial glycaemic response in healthy subjects: a crossover, randomized, controlled study. Sci Rep. 2018;8:13679. doi:.
      68. Campos-Cervantes A, Murillo-Ortiz B, Alvarado-Caudillo Y, et al. Curcumin decreases the oxidative damage indexes and increases the adiponectin levels in serum of obese subjects. Free Radical Biol Med. 2011;S95.
      69. Nieman D, Cialdella-Kam L, Knab A, Shanely R. Influence of red pepper spice and turmeric on inflammation and oxidative stress biomarkers in overweight females: a metabolomics approach. Plant Foods Hum Nutr. 2012;67:415–421.
      70. Mohammadi A, Sahebkar A, Iranshahi M, et al. Effects of supplementation with curcuminoids on dyslipidemia in obese patients: a randomized crossover trial. Phytother Res. 2013;27:374–379.
      71. Sahebkar A, Mohammadi A, Atabati A, et al. Curcuminoids modulate pro-oxidant–antioxidant balance but not immune response to heat shock protein 27 and oxidized LDL in obese individuals. Phytother Res. 2013;27:1883–1888.
      72. Ismail N, Ragab S, El BAky, et al. Effect of oral curcumin administration on insulin resistance, serum resistin and fetuin-a in obese children: randomized placebo-controlled study. Res J Pharm Biol Chem Sci. 2014;5:887–896.
      73. Ganjali S, Sahebkar A, Mahdipour E, et al. Investigation of the effects of curcumin on serum cytokines in obese individuals: a randomized controlled trial. Sci World J. 2014;2014:898361. .
      74. Moohebati M, Yazdandoust S, Sahebkar A, et al. Investigation of short-term supplementation with curcuminoids on circulating small dense low-density lipoprotein concentrations in obese dyslipidemic subjects: a randomized double-blind placebo-controlled cross-over trial. ARYA Atheroscler. 2014;10:280–286.
      75. Ismail N, El Dayam S, Salama E, et al. Impact of curcumin intake on gluco-insulin homeostasis, leptin and adiponectin in obese subjects. Res J Pharm Biol Chem Sci. 2016;7:1891–1897.
      76. Ismail N, El Dayem S, Hamed M, et al. Curcumin intake could lower serum macrophage migration inhibitory factor and monocyte chemoattractant protein-1 levels in obese subjects. Trends Med Res. 2016;11:82–87.
      77. Campbell M, Ouyang A, Krishnakumar I, et al. Influence of enhanced bioavailable curcumin on obesity-associated cardiovascular disease risk factors an arterial function: a double-blinded, randomized, controlled trial. Nutrition. 2019;62:135–139.
      78. Chuengsamarn S, Rattanamongkolgul S, Luchapudiporn R, et al. Curcumin extract for prevention of type 2 diabetes. Diabetes Care. 2012;35:2121–2127.
      79. Tariq S, Imran M, Mushtaq Z, Asghar N. Phytopreventive anticholesterolemic and antilipidemic perspectives of zedoary (Curcuma zedoaria roscoe.) herbal tea. Lipids Health Dis. 2016;15:39–48.
      80. Ferguson J, Stojanovski E, MacDonald-Wicks L, Garg M. Curcumin potentiates cholesterol-lowering effects of phytosterols in hypercholesterolaemic individuals. A randomized controlled trial. Metabolism. 2018;82:22–35.
      81. Thota R, Acharya S, Garg M. Curcumin and/or omega-3 polyunsaturated fatty acids supplementation reduces insulin resistance and blood lipids in individuals with high risk of type 2 diabetes: a randomized controlled trial. Lipids Health Dis 2019. 2019;8:31. doi.org/10.1186/s12944-019-0967-x.
      82. Ferguson J, Wolska A, Remaley A, et al. Bread enriched with phytosterols with or without curcumin modulates lipoprotein profiles in hypercholesterolaemic individuals. A randomised controlled trial. Food Funct. 2019;10:2515–2527. doi:.
      83. Usharani P, Mateen A, Naidu A, Raju Y, Chandra N. Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type-2 diabetes mellitus. Drugs R D. 2008;9:243–250.
      84. Appendino A, Belcaro G, Cornelli U, et al. Potential role of curcumin phytosome (Meriva) in controlling the evolution of microangiopathy. A pilot study. Panminerva Med. 2010;34:1–7.
      85. Khajehdehi P, Pakfetrat M, Javidnia K, et al. Oral supplementation of turmeric attenuates proteinuria, transforming growth factor-ß and interleukin-8 levels in patients with overt type 2 diabetic nephropathy: a randomized, double-blind and placebo-controlled study. Scand J Urol Nephrol. 2011;45:365–370.
      86. Steigerwalt R, Nebbioso M, Appendino G, et al. Meriva®, a lecithinized curcumin delivery system, in diabetic microangiopathy and retinopathy. Panminerva Med. 2012;54(suppl 1):11–16.
      87. Na L, Li Y, Pan H, et al. Curcuminoids exert glucose-lowering effect in type 2 diabetes by decreasing serum free fatty acids: a double-blind, placebo-controlled trial. Mol Nutr Food Res. 2013;57:1569–1577.
      88. Chuengsamarn S, Rattanamongkolgul S, Phonrat B, et al. Reduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: a randomized trial. J Nutr Biochem. 2014;25:144–150.
      89. Na LX, Yan BL, Jiang S, Cui HL, Li Y, Sun CH. Curcuminoids target decreasing serum adipocyte–fatty acid binding protein levels in their glucose-lowering effect in patients with type 2 diabetes. Biomed Environ Sci. 2014;27:902–906.
      90. Neerati P, Devde R, Gangi A. Evaluation of the effect of curcumin capsules on glyburide therapy in patients with type-2 diabetes mellitus. Phytother Res. 2014;28:1796–1800.
      91. Maithili Karpaga Selvi N, Sridhar M, Swaminathan R, Sripradha R. Efficacy of turmeric as adjuvant therapy in type 2 diabetic patients. Ind J Clin Biochem. 2015;30:180–186.
      92. Rahimi H, Mohammadpour A, Dastani M, et al. The effect of nano-curcumin on HbA1c, fasting blood glucose, and lipid profile in diabetic subjects: a randomized clinical trial. Avicenna J Phytomed. 2016;6:567–577.
      93. Jiminez-Osorio A, Garcia-Nino W, Gonzalez-Reyes S, et al. The effect of dietary supplementation with curcumin on redox status and Nrf2 activation in patients with nondiabetic or diabetic proteinuric chronic kidney disease: a pilot study. J Ren Nutr. 2016;26:237–244.
      94. Panahi Y, Khalili N, Sahebi E, et al. Curcuminoids modify lipid profile in type 2 diabetes mellitus: a randomized controlled trial. Complement Ther Med. 2017;33:1–5.
      95. Panahi Y, Khalili N, Sahebi E, et al. Curcuminoids plus piperine modulate adipokines in type 2 diabetes mellitus. Curr Clin Pharmacol. 2017;12:253–258.
      96. Panahi Y, Khalili N, Sahebi E, et al. Antioxidant effects of curcuminoids in patients with type 2 diabetes mellitus: a randomized controlled trial. Immunopharmacology. 2017;25:25–31.
      97. Panahi Y, Khalili N, Sahebi E, et al. Effects of curcuminoids plus piperine on glycemic, hepatic and inflammatory biomarkers in patients with type 2 diabetes mellitus: a randomized double-blind placebo-controlled trial. Drug Res. 2018;68:403–409.
      98. Asadi S, Gholami M, Siassi F, et al. Nanocurcumin supplementation reduced the severity of diabetic sensorimotor polyneuropathy in patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled clinical trial. Complement Ther Med. 2019;43:253–260.
      99. Adibian M, Hodaei H, Nikpayam O, et al. The effects of curcumin supplementation on high-sensitivity C-reactive protein, serum adiponectin, and lipid profile in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Phytother Res. 2019;33:1374–1383. doi:.
      100. Adab Z, Eghtesadi S, Vafa M, et al. Effect of turmeric on glycemic status, lipid profile, hs-CRP, and total antioxidant capacity in hyperlipidemic type 2 diabetes mellitus patients. Phytother Res. 2019;33:1173–1181. doi:.
      101. Hodaei H, Adibian M, Nikpayam O, Hedayati M, Sohrab G. The effect of curcumin supplementation on anthropometric indices, insulin resistance and oxidative stress in patients with type 2 diabetes: a randomized, double-blind clinical trial. Diabetol Metab Syndr. 2019;11:41; https://doi.org/10.1186/s13098-019-0437-7, 11.
      102. Franco-Robles E, Campos-Cervantes A, Murillo-Ortiz B, et al. Effects of curcumin on brain-derived neurotrophic factor levels and oxidative damage in obesity and diabetes. Appl Physiol Nutr Metab. 2014;39:211–218.
      103. Panahi Y, Khalili N, Hosseini S, et al. Lipid-modifying effects of adjunctive therapy with curcuminoids-piperine combination in patients with metabolic syndrome: results of a randomized controlled trial. Complement Ther Med. 2014;22:851–857.
      104. Yang Y, Su Y, Yang H, et al. Lipid-lowering effects of curcumin in patients with metabolic syndrome: a randomized, double-blind, placebo-controlled trial. Phytother Res. 2014;28:1770–1777.
      105. Amin F, Islam N, Anila N, Gilani A. Clinical efficacy of the co-administration of turmeric and black seeds (Kalongi) in metabolic syndrome—a double blind randomized controlled trial—TAK-MetS trial. Complement Ther Med. 2015;23:165–174.
      106. Di Pierro F, Bressan A, Ranaldi D, et al. Potential role of bioavailable curcumin in weight loss and omental adipose tissue decrease: preliminary data of a randomized, controlled trial in overweight people with metabolic syndrome. Preliminary study. Eur Rev Med Pharmacol Sci. 2015;19:4195–4202.
      107. Panahi Y, Hosseini M, Khalili N, et al. Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: a randomized controlled trial and an updated meta-analysis. Clin Nutr. 2015;34:1101–1108.
      108. Panahi Y, Hosseini M, Khalili N, et al. Effects of supplementation with curcumin on serum adipokine concentrations: a randomized controlled trial. Nutrition. 2016;32:1116–1122.
      109. Panahi Y, Hosseini M, Khalili N, et al. Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: a post-hoc analysis of a randomized controlled trial. Biomed Pharmacother. 2016;82:578–582.
      110. Ghazimoradi M, Saberi-Karimian Mohammadi F, et al. The effects of curcumin and curcumin-phospholipid complex on the serum prooxidant-antioxidant balance in subjects with metabolic syndrome. Phytother Res. 2017;31:1715–1721.
      111. Mohammadi A, Sadeghnia H, Saberi-Karimian M, et al. Effects of curcumin on serum vitamin E concentrations in individuals with metabolic syndrome. Phytother Res. 2017;31:657–662.
      112. Selmanovic S, Beganlic A, Salihefendic N, et al. Therapeutic effects of curcumin on ultrasonic morphological characteristics of liver in patients with metabolic syndrome. Acta Inform Med. 2017;25:169–174.
      113. Javandoost A, Afshari A, Saberi-Karimian M, et al. The effects of curcumin and modified curcumin formulations on serum cholesterol ester transfer protein concentrations in patients with metabolic syndrome: a randomized, placebo-controlled clinical trial. Avicenna J Phytomed. 2018;8:330–337.
      114. Mohammadi F, Ghazi-Moradi M, Ghayour-Mobarhan M, et al. The effects of curcumin on serum heat shock protein 27 antibody titers in patients with metabolic syndrome. J Diet Suppl. 2018;16:592–601. doi.org/10.1080/19390211.2018.1472710.
      115. Safarian H, Parizadeh S, Saberi-Karimian M, et al. The effect of curcumin on serum copper and zinc and Zn/cu ratio in individuals with metabolic syndrome: a double-blind clinical trial. J Diet Suppl. 2019;16:625–634. doi.org/10.1080/19390211.2018.1472711.
      116. Saberi-Karimian M, Parizadeh S, Ghayour-Mobarhan M, et al. Evaluation of effects of curcumin in patients with metabolic syndrome. Comp Clin Pathol. 2018;27:555–563.
      117. Cicero A, Sahebkar A, Fogacci F, et al. Effects of phytosomal curcumin on anthropometric parameters, insulin resistance, cortisolemia, and non-alcoholic fatty liver disease indices: a double-blind, placebo-controlled clinical trial [published online February 22, 2019]. Eur J Nutr. 2019. doi.org/10.1007/s00394-019—1916-7.
        118. Rahmani S, Asgary S, Askari G, et al. Treatment of non-alcoholic fatty liver disease with curcumin: a randomized placebo-controlled trial. Phytother Res. 2016;30:1540–1548.
        119. Panahi Y, Kianpour P, Mohtashami R, et al. Curcumin lowers serum lipids and uric acid in subjects with nonalcoholic fatty liver disease: a randomized controlled trial. 2016;68:223–229.
        120. Navekar R, Rafraf M, Ghaffari A, et al. Turmeric supplementation improves serum glucose indices and leptin levels in patients with nonalcoholic fatty liver disease. J Am Coll Nutr. 2017;36:261–267.
        121. Jazayeri-Tehrani S, Rezayat SM, Mansouri S, et al. Nano-curcumin improves glucose indices, lipids, inflammation, and nesfatin in overweight and obese patients with non-alcoholic fatty liver disease (NAFLD): a double-blind randomized placebo-controlled clinical trial. Nutr Metab. 2019;16:8. doi.org/10.1186/s12986-019-0331-1.
        122. Ghaffari A, Rafraf M, Navekar R, et al. Turmeric and chicory seed have beneficial effects on obesity markers and lipid profile in non-alcoholic fatty liver disease (NAFLD). Int J Vitam Nutr Res. 2019;89:293–302. doi.org/10.1024/0300-9831/a000568.
        123. Chasmnian S, Mirhafez S, Dehabeh M, et al. A pilot study of the effect of phospholipid curcumin on serum metabolomic profile in patients with non-alcoholic fatty liver disease: a randomized, double-blind, placebo-controlled trial. Eur J Clin Nutr. 2019;73:1224–1235. doi.org/10.1038/s41430-018-0386-5.
        124. Alwi I, Santoso T, Suyono S, et al. The effect of curcumin on lipid level in patients with acute coronary syndrome. Acta Med Indones J Intern Med. 2008;40:201–210.
        125. Mirzabeigi P, Mohammadpour A, Salarifar M. The effect of curcumin on some of traditional and non-traditional cardiovascular risk factors: a pilot randomized, double-blind, placebo-controlled trial. Iran J Pharm Res. 2015;14:479–486.
        126. Azhdari M, Karandish M, Mansoori A. Metabolic benefits of curcumin supplementation in patients with metabolic syndrome: a systematic review and meta-analysis of randomized control trials. Phytother Res. 2019;33:1289–1301. doi:.
        127. Avansar S. The effects of eight weeks interval training and curcumin consumption on TNF-α and BDNF levels in men with metabolic syndrome. J Ardabil Univ Med Sci. 2017;17:299–310.
        128. Poolsup N, Suksomboon N, Kurnianta P, Deawjaroen K. Effects of curcumin on glycemic control and lipid profile in prediabetes and type 2 diabetes mellitus: a systematic review and meta-analysis. PLoS One. 2019;14:e0215840. doi.org/10.1371/journal.pone.0215840.
        129. Adab Z, Eghtesadi S, Vafa M, et al. Effect of turmeric on body measurement indices, glycemic condition, and lipid profile in hyperlipidemic patients with type 2 diabetes. Iran J Nutr Sci Food Technol. 2013;8:217–227.
        130. Qin S, Huang L, Gong J, et al. Efficacy and safety of turmeric and curcumin in lowering blood lipid levels in patients with cardiovascular risk factors: a meta-analysis of randomized controlled trials. Nutr J. 2017;16:68. doi:.
        131. Sahebkar A. A systematic review and meta-analysis of randomized controlled trials investigating the effects of curcumin on blood lipid levels. Clin Nutr. 2014;33:406–414.
        132. Tabrizi R, Vakili S, Lankarani K, et al. The effects of curcumin on glycemic control and lipid profiles among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. Curr Pharm Design. 2018;24:3184–3199.
        133. Tabrizi R, Vakili S, Akbari M, et al. The effects of curcumin-coontaining supplements on biomarkers of inflammation and oxidative stress: a systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2019;33:253–262.
        134. White C, Pasupuleti V, Roman Y, et al. Oral turmeric/curcumin effects on inflammatory markers in chronic inflammatory diseases: a systematic review and meta-analysis of randomized control trials. Pharmacol Res. 2019;146:104280.
        135. Qin S, Huang L, Gong J, et al. Meta-analysis of randomized controlled trials of 4 weeks or longer suggest that curcumin may afford some protection against oxidative stress. Nutr Res. 2018;60:1–12.
        136. Pagano E, Romano B, Izzo A, Borrelli F. The clinical efficacy of curcumin-containing nutraceuticals: an overview of systematic reviews. Pharmacol Res. 2018;134:79–91.
        137. Sahebkar A. Are curcuminoids effective C-reactive protein-lowering agents in clinical practice? Evidence from a meta-analysis. Phytother Res. 2014;28:633–642.
        138. Atkin S, Katsiki N, Derosa G, et al. Curcuminoids lower plasma leptin concentrations: a meta-analysis. 2017;31:1836–1841.
        139. Chin K. The spice for joint inflammation: anti-inflammatory role of curcumin in treating arthritis. Drug Des Dev Ther. 2016;10:3029–3042.
        140. Akuri M, Barbalho S, Val R, Guiguer E. Reflections about osteoarthritis and Curcuma longa. Pharmacogn Rev. 2017;11:8–12.
        141. Sahebkar A. Curcuminoids in the management of hypertriglyceridaemia. Nat Rev Cardiol. 2014;11:123. doi:.
        142. Jimenez-Osorio A, Monroy A, Alavez S. Curcumin and insulin resistance—molecular targets and clinical evidences. Biofactors. 2016;42:561–580. doi:.
        143. Ganjali S, Blesso C, Banach M, et al. Effects of curcumin on HDL functionality. Pharmacol Res. 2017;119:208–218.
        144. Dadhaniya P, Patel C, Muchhara J, et al. Safety assessment of a solid lipid curcumin particle preparation: acute and subchronic toxicity studies. Food Chem Toxicol. 2011;49:1834–1842.
        145. Storka A, Vcelar B, Klickovic U, et al. Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans. Int J Clin Pharmacol Ther. 2015;53:54–65.
        146. Soleimani V, Sahebkar A, Hosseinzadeh H. Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: review. Phytother Res. 2018;32:985–995.
        147. Cheng A, Hsu C, Lin J, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or premalignant lesions. Anticancer Res. 2001;21:2895–2900.
        148. Tuntipopipat S, Judprasong K, Zeder C, et al. Chili, but not turmeric, inhibits iron absorption in young women from an iron-fortified composite meal. J Nutr. 2006;136:2970–2974.
        149. Smith T, Ashar B. Iron deficiency anemia due to high-dose turmeric. Cureus. 2019;11:e3858. doi:.
        150. Juan H, Terhaag B, cong Z, et al. Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers. Eur J Clin Pharmacol. 2007;63:663–668.
        151. Ikehata M, Ohnishi N, Egami S, et al. Effects of turmeric extract on the pharmacokinetics of nifedipine after a single oral administration in healthy volunteers. J Diet Suppl. 2009;5:401–410.
        152. Volak L, Hanley M, Masse G, et al. Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2012;75:450–462.
        153. Asher G, Spelman K. Clinical utility of curcumin extract. Altern Ther. 2013;19:20–22.
        154. Al-Jenoobi F, Al-Thukir A, Alam M, et al. Effect of Curcuma longa on CYP2D6- and CYP3A4-mediated metabolism of dextromethorphan in human liver microsomes and healthy human volunteers. Eur J Metab Pharmacokinet. 2015;40:61–66.
        155. Bahramsoltani R, Rahimi R, Farzaei M. Pharmacokinetic interactions of curcuminoids with conventional drugs: a review. J Ethnopharmacol. 2017;209:1–12.
        156. Hussaarts K, Hurkmans D, Oomen-de-Hoop E, et al. Impact of curcumin (with or without piperine) on the pharmacokinetics of tamoxifen. Cancer. 2019;11:403–414.
        157. Jurenka J. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev. 2009;14:141–153.
        158. Gota V, Maru G, Soni T, et al. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. J Agric Food Chem. 2010;58:2095–2099.
        159. He S, Chan E, Zhou S. ADME properties of herbal medicines in humans: evidence, challenges and strategies. Curr Pharm Des. 2011;17:357–407.

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