Methods Used for Enhancing the Bioavailability of Oral Curcumin in Randomized Controlled Trials: A Meta-Research Study

It is unknown how randomized controlled trials (RCTs) approach the problem related to curcumin bioavailability. We analyzed methods and reporting regarding the bioavailability of systemic oral curcumin used in RCTs. We searched PubMed on 12 September 2020, to find articles reporting RCTs that used curcumin as an intervention. We extracted data about trial characteristics, curcumin products used, methods for improving curcumin bioavailability, and mentions of curcumin bioavailability. We included 165 RCTs. The most common category of intervention was simply described as “curcumin” or “curcuminoids” without a commercial name. There were 107 (64%) manuscripts that reported that they used methods to enhance the oral bioavailability of curcuminoids used in their intervention; 25 different methods were reported. The most common method was the addition of piperine (23%). Phospholipidated curcumin, a combination of curcumin and turmeric oils, nanomicellar curcumin, and colloidal dispersion of curcumin were the next most common methods. Fourteen trials (8.4%) compared more than one different curcumin product; nine (7.9%) trials compared the bioavailability/pharmacokinetics of curcumin products. In conclusion, a high number of diverse methods were used, and very few trials compared different curcumin products. More studies are needed to explore the comparative bioavailability and efficacy of different curcumin products.

Bioavailability is a term used to describe the percentage, or the fraction, of an administered dose of a xenobiotic that reaches the systemic circulation. Thus, bioavailability is essential in oral dosage form development [5]. Multiple studies have reported a relatively lower bioavailability after oral administration of curcumin [6,7]. Preclinical data and clinical studies on volunteers confirmed a small amount of absorption in intestines, hepatic first-pass effect, and a certain degree of intestinal metabolism as contributors to the poor systemic availability of curcumin when given orally [8].
It has been suggested that formulations that include adjuvants, nanoparticles, liposomes, micelles, and phospholipid complexes should improve bioavailability and enable longer circulation, better permeability, and resistance to curcumin's metabolic processes [9].
A randomized controlled trial (RCT) is a prospective experimental study used to measure the efficacy of an intervention. In an RCT, participants are randomized into multiple arms, which receive different interventions and comparators. Participants are followed and compared. If they are designed adequately, it is considered that RCTs may achieve adequate control over confounding factors to enable an objective comparison of the interventions studied. However, as the RCTs of curcumin are accumulating, it is unknown how those trials approach the problem related to curcumin bioavailability and how it can impact trial results.
This study aimed to analyze whether RCTs of curcumin pay any attention to the bioavailability of systemic oral curcumin, whether trialists attempted to use methods that could improve this bioavailability, and whether they discussed their results in terms of curcumin bioavailability.

Results
The search yielded a total of 319 records, of which we excluded 154 for reasons reported in Supplementary File S1. The remaining 165 studies were included in the analysis. The list and characteristics of included RCTs are reported in detail in Supplementary File S2. Summary characteristics of included studies are shown in Table 1. The included RCTs were published between the years 1980 and 2020. Trials were published by 112 journals, most commonly in the journal Phytotherapy Research (Table 1). Protocol registration was reported in 95 (58 %) studies; among those, most of the RCTs were registered on ClinicalTrials.gov (Table 1). The median number of participants randomized was 60. The median of two study arms were included. The median duration of patient follow-up was 4.5 weeks ( Table 1).
The most common categories of participants included were healthy participants, followed by patients with arthritis, diabetes mellitus type 2, skin diseases, nonalcoholic fatty liver disease, and metabolic syndrome (Table 1). All categories of participants are shown in Supplementary File S2.
Among included 165 trials, there were 184 curcumin interventions, as some trials used more than one curcumin product as a tested intervention. The most common category of curcumin intervention was simply described as "curcumin" or "curcuminoids" without a commercial name (Table 2). Table 2. The most common types of curcumin products used in analyzed trials (N = 165); interventions used in two trials or more are shown. Commercial names of the products are marked with an asterisk. A complete description of curcumin from methods reported in included RCTs (commercial name, details, dose, instructions for use) is reported in detail in Supplementary File S2.
Among the 165 included RCTs, 112 (68%) mentioned the bioavailability of curcumin throughout the manuscript, regardless of the context. The parts of the manuscript where this was most commonly mentioned were the Introduction, Methods, and Discussion. Verbatim extractions of those parts of the text where the bioavailability of curcumin was mentioned are shown in Supplementary File S2.
There were 106 (64%) manuscripts that reported the use of methods to enhance the oral bioavailability of curcuminoids used in their intervention. The trials reported 25 different methods for enhancing the bioavailability of oral curcumin. The most common method was the addition of piperine, used in 23% of the trials. Phospholipidated curcumin, a combination of curcumin and turmeric oils, nanomicellar curcumin, and colloidal dispersion of curcumin were the next most common methods (Table 3). Table 3. Methods used to enhance the oral bioavailability of curcuminoids in analyzed trials (N = 107).

N (%)
Piperine 26 (24) Phospholipidated curcumin 19 (18) Turmeric oils 17 (14) Nanomicellar curcumin 12 (11) Colloidal dispersion of curcumin 12 (11) Nanocurcumin 4 (3.7) Curcumin(oids)-galactomannoside complex 2 (1.9) Curcumin in a turmeric matrix formulation 2 (1.9) Dispersion of curcumin and antioxidants on a water-soluble carrier 2 (1.9) Solid-lipid particle formulation 2 (1. Most trials that used methods for enhanced oral bioavailability of curcumin were published in the most recent analyzed 5 years; only 12 trials using such methods were published before 2014. All trials that mentioned bioavailability did not use methods to enhance the bioavailability, and vice versa. Among the 53 trials that did not mention bioavailability anywhere in the manuscript, 10 (19%) used methods to enhance curcumin bioavailability. Of 112 trials that mentioned bioavailability in the manuscript, 16 (14%) did not report the use of any methods to enhance curcumin bioavailability.
There were 14 (8%) trials that compared more than one type of standardized curcumin product. Most of them compared two curcumin products; while one compared three products, and two compared four products ( Table 4). Nine of those fourteen trials compared the bioavailability or pharmacokinetics of the tested curcumin products. Trials that compared the enhanced versions with the standard curcumin reported that the bioavailability was higher with the enhanced products (Table 4). Six trials compared the effect of supplementation of various curcumin products in individuals with metabolic syndrome, osteoarthritis, or those suffering from experiencing occupational stress-related anxiety and fatigue. Results were heterogeneous, as half of those trials did not demonstrate any superiority of enhanced products on the investigated outcomes (Table 4). To investigate the effects of curcumin on serum copper (Cu), zinc (Zn), and Zn/Cu ratio levels in patients with metabolic syndrome.
Serum Zn concentration was increased significantly in the phospholipidated curcumin and curcumin groups after intervention, and it was significantly higher (p < 0.001) in the phospholipidated curcumin group than in the curcumin group (p < 0.05). The effect of phospholipidated curcumin on zinc was higher than the effect of curcumin because phospholipidated curcumin has better bioavailability than curcumin.

29958053
Curcumin Meriva * To investigate the effects of unformulated curcumin and phospholipidated curcumin on antibody titers to heat shock protein 27 (anti-Hsp 27) in patients with metabolic syndrome (MetS).
Study used phospholipidated curcumin, which is known to be more bioavailable compared to unformulated curcumin, but no significant changes in serum anti-Hsp 27 and anthropometric measures in patients with MetS following supplementation could be found.

Lipisperse * Curcumin
To investigate the pharmacokinetics of a commercially available curcumin extract, with or without the curcumin-LipiSperse ® delivery complex.
The novel delivery system LipiSperse ® is safe in humans, and demonstrates superior bioavailability for the supply of curcumin when compared to a standard curcumin extract.

BioCurc * Curcumin
To assess the bioavailability of a novel curcumin formulation compared to 95% curcumin and published results for various other curcumin formulations.
The novel curcumin liquid droplet micromicellar formulation (CLDM) formulation facilitates absorption and produces exceedingly high plasma levels of both conjugated and total curcumin compared to 95% curcumin. Serum PAB increased significantly in the curcumin group (p < 0.001), but in the phospholipidated curcumin group, elevation of PAB level was not significant (p = 0.053). The results of our study did not suggest any improvement of PAB following supplementation with curcumin in MetS subjects.

28198120
Curcumin-phospholipid complex Curcumin To investigate the effect of curcumin on serum vitamin E levels in subjects with MetS.
Results of the present study did not suggest any improving effect of curcumin supplementation on serum vitamin E concentrations in subjects with MetS.

CGM Curcumin
To investigate the safety, antioxidant efficacy, and bioavailability of CurQfen (curcumagalactomannoside [CGM]), a food-grade formulation of natural curcumin with fenugreek dietary fiber that has been shown to possess improved blood-brain barrier permeability and tissue distribution in rats.
The study demonstrated the safety, tolerance, and enhanced efficacy of CGM in comparison with unformulated standard curcumin. Further comparison of the free curcuminoids bioavailability after a single-dose (500 mg once per day) and repeated-dose (500 mg twice daily for 30 days) oral administration revealed enhanced absorption and improved pharmacokinetics of CGM upon both single-(30.7-fold) and repeated-dose (39.1-fold) administrations. A formulation of curcumin with a combination of hydrophilic carriers, cellulosic derivatives, and natural antioxidants significantly increases curcuminoid appearance in the blood in comparison to unformulated standard curcumin CS, CTR, and CP.

Microencapsulated curcumin Curcumin
To investigate the human bioavailability of curcumin from breads enriched with 1 g/portion of free curcumin (FCB), encapsulated curcumin (ECB), or encapsulated curcumin plus other polyphenols (ECBB) was evaluated.
Curcuminoid encapsulation increased their bioavailability from enriched bread, probably preventing their biotransformation, with combined compounds slightly reducing this effect.

Meriva * Curcumin
To investigate the relative absorption of a standardized curcuminoid mixture and its corresponding lecithin formulation (Meriva) in a randomized, double-blind, crossover human study.
The improved absorption, and possibly also a better plasma curcuminoid profile, might underlie the clinical efficacy of Meriva at doses significantly lower than unformulated curcuminoid mixtures.

28204880
Curcumin Gamma-cyclodextrin complex containing curcumin Meriva * BCM95 * To investigate the bioavailability of a new γ-cyclodextrin curcumin formulation (CW8). This formulation was compared to a standardized unformulated curcumin extract (StdC) and two commercially available formulations with purported increased bioavailability: a curcumin phytosome formulation (CSL), and a formulation of curcumin with essential oils of turmeric extracted from the rhizome (CEO).
The data presented suggest that γ-cyclodextrin curcumin formulation (CW8) significantly improves the absorption of curcuminoids in healthy humans.

27503249
Meriva * C3 complex * To evaluate the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts in a randomized, crossover study When adjusting for curcumin dose, tissue curcumin concentrations were five-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at a steady state in both plasma and rectal tissues.

29027274
Cureit/Acumin * Curcu-Gel * Doctor's Best Curcumin Phytosome * To assess the bioavailability of a completely natural turmeric matrix formulation (CNTMF) and compare its bioavailability with two other commercially available formulations, namely, curcumin with volatile oil (volatile oil formulation) and curcumin with phospholipids and cellulose (phospholipid formulation), in healthy human adult male subjects (15 each group) under fasting conditions.
The results of this study indicate that curcumin in a natural turmeric matrix exhibited greater bioavailability than the two comparator products.

Discussion
This study showed that 68% of RCTs that analyzed the effects of curcumin used methods for enhancing the oral bioavailability of oral curcumin. The most common enhancement method was the addition of piperine to curcumin. Most of the trials that used methods for enhancing the oral bioavailability of curcumin were published in the five most recent analyzed years. However, very few trials (7.9%) compared the bioavailability/pharmacokinetics of various curcumin products.
Oral bioavailability is a crucial aspect of the bio-efficiency of bioactive food ingredients, as it influences the potential health benefits of food [10]. However, many biocomponents have a low oral bioavailability because of their low stability in gastrointestinal fluid and inadequate absorption through the intestinal epithelium [11,12]. Thus, researchers have started studying the possibilities of improving the oral bioavailability of food bioactive ingredients by incorporating bioactive agents into different colloidal delivery systems such as emulsions, nanoemulsions, microemulsions, solid lipid nanoparticles, biopolymer nanoparticles, microgels, et cetera [6,[13][14][15][16].
As curcumin has low aqueous solubility and can be metabolized rapidly by the gastrointestinal system, resulting in low oral bioavailability, multiple pharmaceutical strategies for oral administration of curcumin have also been tested, including solid dispersions, nano/microparticles, polymeric micelles, nanosuspensions, lipid-based nanocarriers, cyclodextrins, conjugates, and polymorphs [17].
It is reasonable to expect that different formulations of curcumin and different methods used to improve its oral bioavailability will impact human clinical trials. In a narrative review published in 2019, Ma et al. presented 39 trials that used curcumin in a tabular form, but without reporting methods for searching the literature and without a clear conclusion regarding the methods used or their comparative advantage [17].
In 2019, Kunnumakkara published a non-systematic analysis of "over 200 clinical studies with curcumin", claiming that the "therapeutic potential of curcumin as demonstrated by clinical trials has overpowered the myth that poor bioavailability of curcumin poses a problem" [18]. However, their study did not report any research methods, analysis methods, or eligibility criteria [18]. Such generic statements cannot be made based on non-systematic narrative literature reviews.
In this study, we analyzed all RCTs indexed until the targeted search date on PubMed that used curcumin to explore methods to enhance its oral bioavailability. In 107 trials that reported using such methods, 25 different methods were described. This is a widely heterogeneous methodological approach, and it is not clear what the comparative efficacy of all those different approaches is. Only 14 out of 165 trials we analyzed compared different curcumin products (from two to four products), and of those 14 trials, 9 compared their bioavailability/pharmacokinetics. Considering the vast heterogeneity of different methods described for enhancing the bioavailability of curcumin, the number of RCTs that have compared bioavailability/pharmacokinetics of different curcumin products is extremely low.
Moreover, six trials that compared different curcumin products have compared their effects on various clinical outcomes regarding efficacy and/or safety. Some of those studies did not find that products with methods that are supposed to enhance availability were better than the standard curcumin. This indicates that we not only need trials that will compare the bioavailability of different methods, but also trials that will compare different curcumin products head-to-head to test their comparative clinical efficacy.
Of note, we found that among 113 trials that mentioned bioavailability in the manuscript, 14% did not report using any methods to enhance curcumin bioavailability. This indicates that some trialists were aware of the issues related to curcumin bioavailability but still chose not to try to enhance it.
While the focus of this study was to analyze aspects related to the bioavailability of curcumin, we noticed poor reporting of investigated interventions. Some studies reported "generic" names or descriptions of the intervention, while some reported commercial names. Some studies reported both, but with an incomplete list or description of the investigated interventions. Furthermore, the trialists interchangeably used the terms curcumin and curcuminoids, even though they are not synonymous. Thus, we would urge trialists to devote more attention to detailed and correct reporting of the intervention that was used in a trial. Transparent reporting will foster the replicability of a trial.
Evidence syntheses from this field of research should compare the effects of different methods for enhancing the oral bioavailability of curcumin in data from clinical trials. Such analysis should involve data extraction on outcomes for efficacy and safety for different indications and performing comparative evaluations between trials that used different methods. However, that was beyond the scope of this study.
This study had several limitations. First, we searched only PubMed to retrieve RCTs on curcumin. Since this was not a systematic review, we used a single search system to retrieve comprehensive datasets of trials to analyze. A recent comparison of 26 different academic search systems that could be used in systematic reviews and meta-analyses showed that PubMed is suitable for use as a principal search system [19]. Second, we used very specific inclusion criteria. However, we provided detailed reasons for excluding the retrieved studies so that our decision-making is transparent.

Study Design
This was a methodological study in which we included RCTs that were indexed on PubMed.

Inclusion Criteria
We included RCTs where curcumin was used via oral ingestion for systemic absorption, and analyzed as an intervention or a comparator, regardless of the type of participants and type of outcomes that were used in a trial. We also included RCT protocols if they were retrieved via our search. We included manuscripts that reported post hoc analyses of previously published RCTs.

Exclusion Criteria
We excluded studies where mixtures of curcumin with other compounds were used as an intervention in a way that the intervention effects could not be attributed clearly to curcumin (for example, curcumin as a spice mixture in food, or as a part of herbal intervention). The only exception was interventions where curcumin was combined with a bioavailability enhancer. We excluded studies using turmeric powders. We excluded studies on animals.
We excluded studies where curcumin was used via administration modes other than oral ingestion for systemic absorption, such as curcumin taken in the mouth only as a local intervention in the oral cavity, or intravenous or rectal application of curcumin.

Search and Screening
We searched PubMed on 12 September 2020 by using the following search syntax: curcumin OR curcuma OR turmeric OR theracurmin OR tetrahydrocurcumin OR NCB-02 OR Curcuma domestica Val. OR Curcuma xanthorrhiza OR diferuloylmethane OR curcuminoids OR Biocurcumax OR biocurcumin OR BCM-95 OR BCM-095, and combined it with the limit for randomized controlled trials.
All bibliographic records that were found with this search were retrieved. Two authors independently screened all records to verify that they indeed fulfilled the inclusion criteria. We then retrieved full texts of all RCTs that were deemed eligible or potentially eligible and repeated screening of full texts against the inclusion criteria. Again, two authors independently screened each full text. Reasons for excluding records from the study were noted. In case of disagreement during the screening of bibliographic records and full texts, two authors resolved discrepancies in opinion via discussion, or if necessary, a third author was included in the decision-making.

Data Extraction
Two authors participated in data extraction for each study; one author conducted the extraction, and the second author verified the extraction. For RCTs retrieved via PubMed, we extracted the following information: the last name of the first author, year of publication, the title of study, trial registration number, number of participants randomized, number of study arms, duration of follow-up, type of participants included, type of curcumin product that was tested (either as an intervention or a comparator), and a complete description of curcumin from the methods. We also extracted any mentions about the bioavailability of curcumin throughout the manuscript, together with the manuscript section where considerations regarding curcumin bioavailability were mentioned. For the type of curcumin that was used, we extracted information for both commercial and generic names of the product, as described in the article.
After data extraction, we categorized the responses and presented the data narratively.

Statistics
Data were presented as numbers and frequencies, median, and range. Microsoft Excel (Microsoft Inc., Redmond, WA, USA) was used for analyses.

Conclusions
The majority of trials reported using methods for enhancing the oral bioavailability of curcumin. However, a large number of diverse methods were used, and very few trials compared different curcumin products. More studies are needed to explore the comparative bioavailability and efficacy of different curcumin products. Funding: The article processing charge for this manuscript was funded by the University of Split Faculty of Science from the institutional financial support awarded to Viljemka Bučević Popović.