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.
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.
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, https://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.
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, https://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, https://links.lww.com/NT/A29.
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, https://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
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#).
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.
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.
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