Safety and Efficacy of Curcumin Products Used as Anti-inflammatory Agents

Curcumin White Paper

1. Introduction
   1. Intro/summary
   2. Motivation, Objectives, Rationale
2. Background
   1. Origin of Turmeric, History, Traditional Use
   2. Ethnobotany, Various species
   3. Chemical Composition of Turmeric and Curcumin
3. Pharmacokinetics and Pharmacodynamics of Curcumin
   1. Metabolism and Absorption
   2. Dose-response relationship and safety
   3. Bioavailability and the use of Adjuvants
      1.    Black pepper (piperine) and Curcumin
      2.    Fat and Curcumin
      3.    Trademarked Curcumin
   4. Potency of Curcumin
4. Medicinal benefits of curcumin
   1. Antioxidant
   2. Inflammation
   3. Immune support
   4. Vasodilator
   5. Anti-bacterial and anti-fungal
   6. Pain relief
5. Review of pre-clinical and clinical studies
   1. Arthritis
   2. Alzheimer’s/Neurodegenerative Diseases
   3. Cancer
   4. Diabetes Mellitus type 2
   5. Cardiovascular disease
   6. Digestive disorders
   7. Obesity
6. Discussion, Conclusion, Future Direction

1. Introduction
   1. Intro/Summary

Modern medicine often reaches back into traditional medicinal practices to pull concepts that have proven successful and need further research to apply them more broadly. Turmeric has been used in traditional medical practices for thousands of years. Curcumin, the powerful component of turmeric, is a recent scientific discovery in the last 100 years and has gained recognition with great potential in modern medical practices without any significant negative side effects.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)} Turmeric has gained its reputation as one of the most powerful healing spices because of its anti-oxidant and anti-inflammatory effects – now known to be attributable to curcumin. It is therefore a promising agent used for the treatment and prevention for much of the disease burden affecting the majority of the world’s population today – health conditions resulting from chronic oxidative stress and chronic inflammation, such as cancer, diabetes, and obesity.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)}

Turmeric (curcuma longa) has been used as a dietary spice, food preservative and coloring agent or thousands of years in Asian countries^{(Chattopadhyay, Biswas, Bandyopadhyay, & Banerjee, 2004)(Gupta, Patchva, Koh, & Aggarwal, 2012)}.  [Put reference as superscript AFTER the period.  [Once the draft is completely done we need to do this, and order them smallest to highest (e.g. not have 5, 4, 7) —-  And pull multiple references together like this: 1-4 instead of 1, 2, 3, 4]   Ayurveda, an ancient system of health and healing from India, has used turmeric as a home remedy for various diseases, including digestive disorders, ulcers, hepatic disorders, anorexia, diabetic wounds, jaundice, arthritis, acnes, skin and eye infections, respiratory infections, and sinusitis.^{(Ammon, Anazodo, Safayhi, Dhawan, & Srimal, 1992)} Today, turmeric is used as a medicinal, culinary as well as cosmetic supplement throughout the world.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} It is marketed in several forms including capsules, tablets, ointments, energy drinks, soaps, and cosmetics.^{(Gupta, Patchva, Koh, & Aggarwal, 2012)}

Turmeric has a number of different compounds that are supportive to the body. The main constituents include three curcuminoids: curcumin, demethoxycurcumin, and bisdemethoxycurcumin (Figure 1), with curcumin being the most effective at controlling inflammation, cell growth, and apoptosis.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} In recent years, research interest in this pleiotropic molecule has increased dramatically and – with its great potential to act as an anti-oxidant and anti-inflammatory agent – is now being explored as “a new drug” to help prevent or even treat diabetes, cancer, arthritis, and neurodegenerative diseases just to name a few.^{(Gupta, Patchva, Koh, & Aggarwal, 2012),(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} Research has shown that curcumin can modulate multiple signaling pathways in either a direct or indirect manner. There is evidence that this polyphenol possessed biological activities in animal models of many human diseases. In human clinical trials, curcumin has been found to be safe and efficacious, and the U.S. Food and Drug Administration has approved curcumin as a “generally regarded as safe” compound.^{(Gupta, Patchva, Koh, & Aggarwal, 2012)}

2. Objectives

Today in modern medicine, steroids and nonsteroidal anti-inflammatory drugs (NSAIDS) are the most commonly used anti-inflammatory agents. However, there are numerous side effects associated with these products, especially when used long-term.^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)} There is evidence that curcumin products can be effective for the treatment and prevention of diseases due to inflammatory disorders. Therefore, our aim is to outline the safety and efficacy of curcumin products used as anti-inflammatory agents and how the effectiveness compares to the use of NSAIDS.

 

3. Motivation, Rationale

Scientific research spanning more than four decades has confirmed the diverse pharmacological effects of curcumin and established its ability to act as a potential therapeutic agent against several chronic diseases.^{(Aggarwal, Kumar, & Bharti, Anticancer potential of curcumin: Preclinical and clinical studies, 2003)(Wilken, Veena, Wang, & Srivatsan, 2011)(Grykiewicz & Silfirski, 2012)(Esatbeyoglu, Huebbe, Insa, DawnChin, Wagner, & Rimbach, 2012) (Gupta, et al., 2011)(Priyadarsini, Chemical and structural features influencing the biological activity of curcumin, 2013)} Since the late 1990’s, over 7000 articles have discussed the molecular structure of curcumin that could be attributable to its medicinal benefits and its interaction with multiple signaling pathways modulating inflammatory activities.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} Numerous in-vitro and pre-clinical studies have explored the role of curcumin in various chronic diseases, which have generated extensive evidence for the potential health benefits of curcumin.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015)} However, results from early phase in-human clinical trials are inconclusive.^{(Aggarwal, et al., 2006)(Hsu & Cheng, 2007) (Chattopadhyay, Biswas, Bandyopadhyay, & Banerjee, 2004)} Over 100 clinical trials have been conducted to clarify the link between curcumin, inflammation, and chronic diseases; but many trials were preliminary in nature or have administered investigational compounds with varying formulations, making comparability of results across trials difficult.^{(He, Yue, Zheng, Zhang, Chen, & Du, 2015) (Hsu & Cheng, 2007)} Therefore, in this paper, we will summarize what is known about curcumin today and we will try to identify the combination of molecules that are most promising in delivering the maximum health benefits. Furthermore, we will shed light on suggested future research efforts needed to be evaluate the efficacy of the most relevant formulation.

Claims have been made that turmeric helps with prevention and treatment of a number of health issues. This paper aims to address the diseases where these claims have been substantiated by proper clinical research and there is evidence to support which formulations are most effective.  Claims that are not substantiated due to lack of clinical research shed light on areas of where more research efforts are needed.  Many trials are preliminary in nature with small sample sizes, and comparability across trials is limited due to varying pre-and post-study measurement metrics and the use of varying curcumin formulations. Most studies compare a new product to plain curcumin that is already known to have low bioavailability. A better comparison group for superiority studies would be the use of bioavailable curcumin such as combination product of curcumin and piperine.

Figure 1: Chemical structure of curcumin, demethoxycurcumin, and bisdemethoxycurcumin.^{(Monton, Charoenchai, Suksaeree, & Sueree, 2016)}

2. Background
   1. Origin of Turmeric, History, Traditional Use

Ayurveda, a traditional system of medicine in India, has used turmeric for over 4000 years. ^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)(Prasad & Aggarwal, 2011)} The ancient medical practices valued turmeric for its bitter, astringent qualities and its healing and cooling effects on the body.^{(Velayudhan, Dikshit, & Nizar, 2012)} Traditionally, turmeric is used for a wide variety of medical issues, including topically as an anti-septic and for wound healing, or ingested to promote digestion, control diabetes, prevent cancer, or treat microbial infections and inflammation, just to name a few.^{(Velayudhan, Dikshit, & Nizar, 2012)}

There is evidence that use of turmeric began in India in ancient times during religious worships by the pre-Aryans. It soon became a commodity of trade as a coloring agent as well as a condiment and it is believed to have spread from South East Asia to nearby Indochina, China, Japan, and other South Pacific Islands by 700 AD. From there, the spread continued to West and East Africa during 12^th century, and reached Central America and the Caribbean by the 19^th century.^{(Velayudhan, Dikshit, & Nizar, 2012)(Prasad & Aggarwal, 2011)} In 1280, Marco Polo described this spice as “a vegetable that exhibited qualities similar to that of saffron”.^{(Prasad & Aggarwal, 2011)} Today, Turmeric is widely cultivated in tropical areas and is referred to by different names in different cultures.^{(Prasad & Aggarwal, 2011)} Almost 94% of the world’s total turmeric production is cultivated in India on about 150,000 hectares of land, making it the largest producer of turmeric in the world.^{(Velayudhan, Dikshit, & Nizar, 2012)} The majority is consumed in India’s domestic market, while only 8% of its production is exported annually.^{(Velayudhan, Dikshit, & Nizar, 2012)} Indian turmeric is considered the best in the world because of its inherent qualities and high curcumin content – the important bioactive ingredient with great medicinal potential.^{(Prasad & Aggarwal, 2011)}

In India and China, turmeric is used as a folk remedy to treat over 50 diseases, including infectious diseases like chicken pox, measles, and the common cold. Traditional healers have used turmeric as an antacid to help with digestive problems, in bandages to enhance wound healing, as an analgesic to relieve headaches, a vasodilator to promote circulation, and as a decongestant to clear nasal passages. However, turmeric has gained its reputation as one of the most powerful healing spices because of its anti-oxidant and anti-inflammatory properties. Most of the disease burden affecting the majority of the world’s population today is due to chronic oxidative stress and chronic inflammation. ^{(Aggarwal & Yost, Healing Spices, 2011)} Medical preparations with curcumin can thus be of paramount value to our population’s health.

The use of curcumin in western medical practices was first reported in the early 20^th century. Curcumin was first isolated in 1815 by Vogel and Pelletier; its chemical structure was determined in 1910 by J. Milobedzka and V. Lampe in Germany. Its use in biliary diseases was documented in 1937 (67 patients treated), its antibacterial action in 1949 and its antidiabetic effects were first documented in 1972.^{(Aggarwal & Sung, Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets, 2009)}

2. Ethnobotany

Turmeric (genus Curcuma Longa) is an herbaceous perennial plant with a short stem, large oblong leaves, and oblong tuberous branched rhizomes; those are brownish yellow in color with a dull orange interior (image 1).^{(Velayudhan, Dikshit, & Nizar, 2012)(Prasad & Aggarwal, 2011)} It is native to tropical South Asia and botanically related to ginger (Zingiberaceae family).^{(Velayudhan, Dikshit, & Nizar, 2012)(Prasad & Aggarwal, 2011)} The plant contains many taxa of economic, medicinal, and cultural importance; as many as 133 species of Curcuma have been identified worldwide.^{(Prasad & Aggarwal, 2011) (Velayudhan, Dikshit, & Nizar, 2012)} The wild turmeric is called C. aromatica and the domestic species is called C. longa.^{(Chattopadhyay, Biswas, Bandyopadhyay, & Banerjee, 2004)} The taxonomic position of Turmeric is displayed in table 1.

Turmeric is derived from the rhizomes, for which the plants are harvested annually.^{(Prasad & Aggarwal, 2011)} In modern day processing, the rhizomes are boiled for several hours in 0.05 – 0.1% alkaline water and then dried, with a final moisture content of 8% – 10%.^{(Prasad & Aggarwal, 2011)} Turmeric powder maintains its classic bright orange color indefinitely, but deterioration over time may cause a loss in flavor. Used by different cultures in many countries, turmeric is referred to by different names. In North India, turmeric is commonly called “haldi”; in South India it is called “manjal”. The word turmeric is derived from Latin “terra merita” which means “meritorious earth”, referring to the color of ground turmeric and its resemblance with a mineral pigment.^{(Prasad & Aggarwal, 2011)}

3. Chemical Composition of Turmeric and Curcumin

Turmeric

The turmeric rhizome is extremely rich in curcuminoid polyphenol anti-oxidants that give it a classic yellow color.  Depending on its origin and the soil conditions where it is grown, turmeric contains 2%-9% curcuminoids.^{(Priyadarsini, The Chemistry of Curcumin: From Extraction to Therapuetic Agent, 2014)} The principal curcuminoid is curcumin (diferuloylmethane, also called curcumin I and natural yellow 3) which is responsible for much for the health benefits attributed to turmeric.  The other 2 curcuminoids are desmethoxycurcumin (DMC), also called curcumin II and bis-desmethoxycurcumin (BDMC), also called curcumin III. ^{(Priyadarsini, The Chemistry of Curcumin: From Extraction to Therapuetic Agent, 2014) (Aggarwal, et al., 2006)} Research investigating whether all three analogues exhibit equal activity are inconclusive. Although in most systems curcumin was found to be most potent, in some systems bisdemethoxycurcumin was found to exhibit higher activity. There are also suggestions that the mixture of all three is more potent than either one alone.^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)} There is evidence that the presence of desmethoxycurcumin and bis-desmethoxycurcumin have synergistic effect on the anti-inflammatory activity of curcumin.^{(Ruby, Kuttan, Dinesh Babu, Rajasekharan, & Kuttan, 1995)}

Turmeric contains protein (6.3%), fat (5.1%), minerals (3.5%), carbohydrates (69.4%) and moisture (13.1%).  The essential oil (5.8%) obtained by steam distillation of rhizomes has α-phellandrene (1%), sabinene (0.6%), cineol (1%), borneol (0.5%, zingiberene (25%) and sesquiterpines (53%).^{(Kapoor, 1990)}

Curcumin

Curcumin was first isolated from Turmeric in 1815 and identified as (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl) hepta-1,6-diene-3,5-dione, with molecular formula C₂₁H₂₀O₆, a polyphenol also known as diferuloyl methane. It is a lipophilic molecule with a molecular weight of 368.38 g/mol, and melting point of 183°C. It appears as yellow-orange powder and is soluble in ethanol, dimethylsulfoxide, and acetone.^{(Priyadarsini, The Chemistry of Curcumin: From Extraction to Therapuetic Agent, 2014) (Aggarwal, et al., 2006)} It is a symmetric molecule with three chemical entities in its structure: two aromatic ring systems containing o-methoxy phenolic groups, connected by a seven carbon linker consisting of an α,β-unsaturated β-diketone moiety. ^{(Priyadarsini, The Chemistry of Curcumin: From Extraction to Therapuetic Agent, 2014)} Curcumin is a tautomeric compound existing in enolic form in organic solvents and as a keto form in water. Its properties are summarized in Table 2; ^{(Priyadarsini, The Chemistry of Curcumin: From Extraction to Therapuetic Agent, 2014)} the chemical structure of curcumin in Enol form is given in figure 1.

 

about 200 years ago, more improved and advanced extraction methods are still being reported, even after two centuries.^{(Priyadarsini, The Chemistry of Curcumin: From Extraction to Therapuetic Agent, 2014)} Solvent extraction followed by column chromatography has been the most commonly employed method reported for separating curcumin from turmeric, and several polar and non-polar organic solvents have been used, including hexane, ethylacetate, acetone, methanol, etc. Of the organic solvents employed, ethanol has been found to be the most preferred solvent for extracting curcumin.  Although chlorinated solvents extract curcumin very efficiently from turmeric, they are not commonly employed due to their non-acceptability in the food industry. ^{(Priyadarsini, The Chemistry of Curcumin: From Extraction to Therapuetic Agent, 2014)}

Commercial curcumin contains about 77% curcumin, 17% of DMC, and 3% of BDMC. ^{(Aggarwal & Sung, Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets, 2009)(Aggarwal, et al., 2006)} In DMC, one methoxy group is absent; in BDMC, the methoxy group is absent from both the aryl rings (Figure 2 in Appendix). There is currently still no consensus as to the most effective preparation for human use and there is no explicit evidence that shows a correlation between the molecular properties of curcumin or its analogues with their biological effects. While several groups have studied the differential bioactivities of these different analogues, no single curcuminoid shows overall highest potency.^{(Epstein, Sanderson, & MacDonald, 2010)} Differential efficacy varies widely according to the cell type, function, disease system and organism in question.^{(Anand, et al., 2008)(Epstein, Sanderson, & MacDonald, 2010)} Commercially available curcumin preparations are largely derived from natural curcumin sources and therefore contain the three main curcuminoids in approximately the previously mentioned proportions. Indeed, some data suggest that such a mixture of curcuminoids have synergistically greater activity than any of their individual elements.^{(Sandur, et al., 2007)(Epstein, Sanderson, & MacDonald, 2010)}

Some studies have shown, however, that curcumin can be more active than DMC or BDMC.^{(Sandur, et al., 2007)} Studies indicate that bis-a,b-unsaturated b-diketone, two methoxy groups, two phenolic hydroxy groups and two double-conjugated bonds might play an essential part in the anti-proliferative and anti-inflammatory activities assigned to curcumin. Various preclinical and clinical studies indicate that curcumin has potential therapeutic value against most chronic diseases including neoplastic, neurological, cardiovascular, pulmonary, metabolic and psychological diseases.^{(Aggarwal & Sung, Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets, 2009)} How curcumin manifests these pharmacological effects in vitro and in vivo is discussed in the next chapter.

Curcumin-free turmeric:

Recent research has identified numerous chemical entities from turmeric other than curcumin. It is unclear whether all of the activities ascribed to turmeric are due to curcumin or whether other compounds in turmeric can manifest these activities uniquely, additively, or synergistically with curcumin. However, studies have indicated that turmeric oil, present in turmeric, can enhance the bioavailability of curcumin. Studies over the past decade have indicated that curcumin-free turmeric components possess numerous biological activities including anti-inflammatory, anti-cancer, and anti-diabetic activities. In China, elements derived from turmeric are approved for the treatment of cancer.^{(Aggarwal, Yuan, Li, & Gupta, 2013)}

3. Pharmacokinetics and Pharmacodynamics of Curcumin

The safety profile of curcumin ingestion is well established. Phase 1 clinical trials have shown that doses as high as 12mg/day were well tolerated in humans. Similarly, the efficacy of curcumin in various diseases, e.g. cancer, has been well established.^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)(Anand, Kunnumakkara, Newman, & Aggarwal, 2007)} The pharmacological safety and efficacy of curcumin makes it a potential compound for treatment and prevention of a wide variety of human diseases. In spite of its efficacy and safety, curcumin has not yet been approved as a therapeutic agent, and the relative bioavailability of curcumin has been highlighted as a major problem for this.^{(Anand, Kunnumakkara, Newman, & Aggarwal, 2007)} Moreover, not only curcumin alone, but also its analogues DMC and BDMC and their metabolites have become the subjects of controversy due to widely reported poor bioavailability, rapid metabolism and excretion, and contrasting claims about the pharmacokinetic benefits of different delivery systems. Presently, there is no consensus regarding how to evaluate the comparative absorption and utilization of commercially available curcumin products and there is no established metric for determining the cost–benefit ratio of various approaches to oral delivery.^{(Douglass & Clouatre, 2015)} However, numerous pre-clinical studies have revealed the great diversity of curcumin’s pharmacological properties, providing evidence that there the high potential for curcumin’s medical benefits in humans once bioavailability is enhanced.

In this chapter, we will discuss in detail what is known about the metabolism and absorption of curcumin, its bioavailability, factors controlling bioavailability, and the means to improve the bioavailability of curcumin.

1. Metabolism and Absorption

Curcumin is a lipophilic polyphenol that is nearly insoluble in water but is relatively stable in the acidic pH of the stomach.^{(Jurenka, 2009)} When administered orally, curcumin is metabolized into curcumin glucuronide and curcumin sulfonate. However, when administered systemically or intraperitoneally, it is metabolized into tetrahydrocurcumin, hexahydrocurcumin, and hexahydrocurcuminol (Figure 2 in appendix). Tetrahydrocurcumin has been shown to be active in some systems and not in others. Whether other metabolites of curcumin exhibit biological activity is not known.^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)}

Extensive research over the past several years has confirmed the diverse pharmacological effects of curcumin and explored the induced beneficial effects on numerous health issues.^{(Priyadarsini, The Chemistry of Curcumin: From Extraction to Therapuetic Agent, 2014)} Curcumin appears to possess a spectrum of pharmacological properties, primarily because of its inhibitory effects on metabolic enzymes. Studies have revealed that curcumin has antioxidant, antibacterial, antifungal, antiviral, anti-inflammatory, anti-proliferative and pro-apoptotic effects.^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007) (Aggarwal & Sung, Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets, 2009)} How a single agent could exhibit all these effects is still under investigation today. Numerous molecular targets for curcumin have been identified over the years. These targets fall into two categories: 1) targets to which curcumin directly binds and modulates their activity (Table 2 in appendix) and 2) those of which modulation of activity is indirect or secondary.^{(Aggarwal & Sung, Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets, 2009)} These pleiotropic effects of curcumin are thought to be due to its ability to bind to a number of different molecules, including: serum albumin, 5-LOX, xanthine oxidase, thioredoxin reductase, iron, COX-2, IKK, p-lycoprotein, GST, PKA, PKC, cPK, PhK, autophosphorylation-activated protein kinase, pp60c-src  tyrosine kinase, Ca2+-dependent protein kinase (CDPK), Ca2+-ATPase of sarcoplasmic reticulum, aryl hydrocarbon receptor, rat river cytochrome p450s, Topo II isomerase, inositol 1,4,5- triphosphate receptor, and glutathione.^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)} A full list of molecules that curcumin can bind to is displayed in Figure 4 (appendix).

Although curcumin has shown therapeutic efficacy against many human health issues, one of the major problems with curcumin is its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid systemic elimination.^{(Jurenka, 2009)} Therefore, efforts have been made to improve curcumin’s bioavailability by improving these features. Adjuvants that can block the metabolic pathway of curcumin have been most extensively used to increase the bioavailability of this polyphenol. For instance, in humans receiving a dose of 2 g curcumin alone, serum levels have been either undetectable or very low, but administration piperine as an adjuvant to enhance bioavailability was associated with an increase of 2000% in the bioavailability of curcumin.^{(Gupta, Patchva, Koh, & Aggarwal, 2012)(Shoba, Joy, Joseph, Majeed, Rajendran, & Srinivas, 1998)} Furthermore, the effect of piperine in enhancing curcumin’s bioavailability has been shown to be much greater in humans than in animal models.^{(Anand, Kunnumakkara, Newman, & Aggarwal, 2007)(Gupta, Patchva, Koh, & Aggarwal, 2012)} Other promising approaches to increase the bioavailability of curcumin include use of nanoparticles, liposomes, micelles, phospholipid complexes, and structural analogues, as described further in Section 3.4.^{(Gupta, Patchva, Koh, & Aggarwal, 2012)}

Rapid degradation and metabolism of curcuminoids, both in the intestine and in the liver, seems to be the biggest limitation with oral consumption of curcumin compounds.^{(Ireson, et al., 2002)(Pan, Huang, & Lin, 1999)(Douglass & Clouatre, 2015)} Non-enzymatic degradation occurs via auto-oxidation and pH-dependent lability. Enzymatic conversion to water-soluble metabolites via beta-glucuronidase and sulfatase occurs quickly; in vitro studies using isolated rat liver cells indicate 90% curcuminoid metabolism via these two mechanisms after just 30 minutes.^{(Douglass & Clouatre, 2015)} All curcuminiods, curcumin, DMC, and BDMC contain two phenolic hydroxyl groups, and thus there is more than one locus amenable to conjugation with glucuronide and sulfate groups.^{(Douglass & Clouatre, 2015)} Only monoglucuronides, monosulfates, and sulfate-glucuronides (one of each) are typically observed as a result of human metabolism.^{(Vareed, et al., 2008)(Douglass & Clouatre, 2015)} For curcumin, this leads to the metabolites curcumin monoglucuronide, curcumin monosulfate, and curcumin sulfate-glucuronide. However, Douglass et al. found that the phenolic groups are not the only parts of the molecule in curcuminoids susceptible to biotransformation.^{(Douglass & Clouatre, 2015)} Other sections of the molecule are susceptible to both conjugation and reduction. Reduction results in colorless compounds, such as dihydrocurcumin, tetrahydrocurcumin, and hexahydrocurcumin, by destroying the extended conjugated system responsible for the typical yellow-orange color of curcuminoids.^{(Douglass & Clouatre, 2015)} These reduced curcumin metabolites are also subject to conjugation with glucuronides or sulfate groups. In the liver, alcohol dehydrogenase and glutathione S-transferase, but not cytochrome p450 enzymes, have been credited with transforming curcuminoids into the reduced curcuminoid metabolites; lipoxygenases also appear to play a role.^{(Douglass & Clouatre, 2015)} All these findings are plausible explanations for the limited bioavailability and poor absorption of pure curcumin. However, these data also point to the areas that could be promising targets for future research efforts on increasing bioavailability.

2. Dose-response relationship and safety

A comprehensive dose-response relationship of curcumin is not yet well established. Many trials in humans have been conducted, but results are inconsistent and more research assessing its pharmacological activity is needed in order to gain a better understanding of the true dose-response relationship of curcumin. However, many studies have shown positive effects of curcumin in a number of health conditions. Data obtained from observational studies suggest that curcumin might possess pharmacological activity even at low oral doses.^{(Sharma, Steward, & Gescher, 2007)} The optimum dose for disease treatment and prevention is still unknown. However, safety studies have shown that long term use of curcumin appears to be safe. No acute or chronic toxicity has been shown in animal models, even at high doses. Similarly, mutagenicity and reproductive toxicity have not been observed in rodents. In humans, several studies have demonstrated minimal toxicity with moderate doses of curcumin.^{(Asher & Spelman, 2013)} Clinical trials have used pharmacologically effective doses of curcumin that exceed normal dietary intake. Phase I clinical trials have shown that dosages of 12g of curcumin daily over a period of 3 months is well tolerated in humans.^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)(Lao, et al., 2006)} In 2 out of 15 subjects, however, the daily intake of curcumin led to diarrhea (grade 1—2), and in one subject to nausea (grade 2). The safety of high curcumin doses (12 g per day) was also assessed in an investigation by Lao et al. They found that high dose curcumin treatment caused diarrhea, skin rash, headaches (grade 1), and yellow-colored feces in 7 out of the 24 subjects included.^{(Lao, et al., 2006)}

Another indicator for its pharmacological safety is that serum levels tend to be low, which has also led to the notion that curcumin has low bioavailability. However, there is evidence that piperine used as an adjuvant can enhance the bioavailablity of curcumin by suppressing its glucuronidation in the liver and intestine, as explained in later chapters.^{(Aggarwal, Sundaram, Malani, & Ichikawa, 2007)}

Additionally, epidemiological data suggest that the daily consumption of turmeric is generally safe as it is consumed daily in India and several other Asian countries. Indeed, the maximum daily intake of turmeric in Nepal is about 1.5 g (which corresponds to ca. 50 mg curcumin) and in India can be up to 2.0–2.5 g (which corresponds to a maximum of ca. 100 mg curcumin).^{(Esatbeyoglu, Huebbe, Insa, DawnChin, Wagner, & Rimbach, 2012)}

It can thus be concluded that dietary curcumin has only very low or no toxicity. However, minor side effects caused by very high doses of curcumin, such as those used in clinical studies, cannot be completely ruled out. As such, the safety of adding curcumin to functional foods and dietary supplements should be rigorously assessed and should not exceed 12g per day.^{(Esatbeyoglu, Huebbe, Insa, DawnChin, Wagner, & Rimbach, 2012)} In the United States, the Food and Drug Administration has approved curcumin as a “generally regarded as safe” compound.^{(Gupta, Patchva, Koh, & Aggarwal, 2012)}

3. Bioavailability and the use of Adjuvants

The absorption, biodistribution, metabolism, and elimination studies of curcumin have, unfortunately, shown only poor absorption, rapid metabolism, and elimination of curcumin as major reasons for poor bioavailability of this interesting polyphenolic compound. Some of the possible ways to overcome these problems are discussed below. Adjuvants, which can block metabolic pathways of curcumin, are one of the major means that are being used to improve its bioavailability. Nanoparticles, liposomes, micelles, and phospholipid complexes are other promising novel formulations, which appear to provide longer circulation, better permeability, and resistance to metabolic processes. Lower serum and tissue levels of curcumin irrespective of the route of administration, rapid metabolism and elimination are major factors decreasing the bioavailability of curcumin.^{(Anand, Kunnumakkara, Newman, & Aggarwal, 2007)}

In the past decade, a significant amount of research efforts have been devoted to the development of curcumin formulations that can overcome poor bioavailability, stability limitations, and rapid metabolism (more under Section 3.4). The rationale for attempting to overcome the bioavailability and metabolic hurdles not only includes the issue of achieving therapeutic blood levels, but it also focuses on 2 additional questions: 1) whether higher concentrations of unmetabolized, i.e. free, curcuminoids in vivo will show the protective and therapeutic effects as demonstrated for curcuminoids in vitro and 2) whether curcuminoid metabolites have the same, diminished, and/or different biological utilities compared to the native curcuminoids. Logically, achieving significant and consistently measureable serum levels of free curcuminoids and/or their conjugates and metabolites is a necessary first step for exploring these other issues. Research and development efforts have excessively explored a number of methods seeking to modulate the pharmacokinetic and delivery profile of curcuminoids.^{(Anand, Kunnumakkara, Newman, & Aggarwal, 2007)(Kumar, Ahuja, Ali, & Baboota, 2010)} These strategies can be grouped into 4 broad classes:

1) glucuronidation/metabolism interference via adjuvants (see Section 3.3.1 on piperine)

2) liposomes, micelles, and phospholipid complexes; (see Section 3.3.2 on fat, and Section 3.4 on Longvida®)

(3) nanoparticles; (see Section 3.4 on Theracurmin®)

(4) emulsifying or dispersing agents (see Section 3.4 on BCM-95®).^{(Anand, Kunnumakkara, Newman, & Aggarwal, 2007)(Douglass & Clouatre, 2015)}

These 4 classes are not exhaustive and can work in combination, especially when specific tissues are being targeted, but they do exemplify a variety of the strategies that are being evaluated in multiple areas of the development of medicinal curcumin products. ^{(Yallapu, Jaggi, & Chauhan, 2012)(Dhule, et al., 2012)} Even though each of these strategies is intended to overcome the issue of low bioavailability, based on e.g. poor water solubility, particle size issues, and/or instability in certain digestive environments, it is expected that combination delivery strategies – i.e. strategies that combine more than one basic method – may produce additive benefits with regard to absorption.^{(Douglass & Clouatre, 2015)}

1.   Black Pepper (piperine) and Curcumin

Pharmacokinetic properties of curcumin indicate that after oral ingestion of curcumin, it is poorly absorbed and only traces of the compound appear in the blood, while most of it is excreted in the feces.^{(Shoba, Joy, Joseph, Majeed, Rajendran, & Srinivas, 1998)} The transformation of curcumin into a metabolite during absorption and its glucuronidation in the liver are probably responsible for its low concentration in blood.^{(Shoba, Joy, Joseph, Majeed, Rajendran, & Srinivas, 1998)} Because of curcumin’s rapid plasma clearance and conjugation, its therapeutic usefulness has been somewhat limited, leading researchers to investigate the benefits of complexing curcumin with other substances to increase systemic bioavailability. One of the substances that has been studied is the alkaloid piperine, a constituent from black pepper and long pepper (Piper nigrum and Piper longum, respectively), and a known inhibitor of glucuronidation. For example, one study in humans showed that 20 mg piperine given in conjunction with 2 g curcumin increased serum curcumin bioavailability 20-fold, which was attributed to piperine’s inhibition of hepatic glucuronidation and intestinal metabolism.^{(Jurenka, 2009)}

Both black pepper and long pepper have been in used as spices from ancient times throughout the world. A major component of the Piper species is the alkaloid piperine (1-piperoylpiperidine), which has been reported to enhance the bioavailability of drugs – not just of curcumin – by inhibition of glucuronidation in the liver and small intestine.^{(Shoba, Joy, Joseph, Majeed, Rajendran, & Srinivas, 1998)} Piperine is a known potent inhibitor of drug metabolism, and glucuronidation altering the disposition and bioavailability of a large number of drugs. Based on evidence that piperine helps with the metabolism of other drugs, it appeared plausible that piperine can have a similar effect with curcumin, since piperine is a known hepatic and intestinal metabolic inhibitor.^{(Shoba, Joy, Joseph, Majeed, Rajendran, & Srinivas, 1998)}. Shoba at al demonstrated that the feasibility of this approach in both rats and humans.^{(Shoba, Joy, Joseph, Majeed, Rajendran, & Srinivas, 1998)} Study results demonstrated that piperine enhanced the oral bioavailability of curcumin in both rats and humans at doses without visible adverse side effects. When 20mg of piperine was administered orally with 2 gm of curcumin to volunteers, serum levels were significantly enhanced after one hour, increasing total bioavailability by 20-fold. No toxicity was observed in the 10 subjects who participated in this study.^{(Shoba, Joy, Joseph, Majeed, Rajendran, & Srinivas, 1998) (Ringman, Frautschy, Cole, Materman, & Cummings, 2005)} Additional evidence that piperine increases the bioavailability of other drugs, such as propranolol and theophylline, is available.^{(Shoba, Joy, Joseph, Majeed, Rajendran, & Srinivas, 1998)}

In conclusion, the study shows that piperine enhances the serum concentration and bioavailability of curcumin in rats and humans probably due to increased absorption and reduced metabolism. ^{(Shoba, Joy, Joseph, Majeed, Rajendran, & Srinivas, 1998)} Piperine may thus be seen as the key to increasing the enhancing the medicinal potential of curcumin products.

2.   Fat and Curcumin

Since curcumin is a lipophilic molecule, the combined ingestion with fat can be highly supportive for its proper absorption into the body. Because of this hydrophobic nature, its bioavailability is poor after oral administration and therefore needs a carrier vehicle to transport to the desired targets. ^{(Anand, Kunnumakkara, Newman, & Aggarwal, 2007) (Kunwar, Barik, Pandey, & Priyadarsini, 2006)} Curcumin has preferential interaction with serum albumins and lipid membranes.^{(Kunwar, Barik, Pandey, & Priyadarsini, 2006)} Liposomes and serum albumins are some of the most commonly used transporting vehicles for drugs, proteins, hormones, diagnostic agents etc., because they can carry both hydrophilic and hydrophobic molecules.^{(Anand, Kunnumakkara, Newman, & Aggarwal, 2007) (Kunwar, Barik, Pandey, & Priyadarsini, 2006)} Liposomes are relatively easy to prepare, biodegradable, and have potential for high drug loading capacity. Serum albumin is the most abundant of the proteins, circulated several times in the blood. Both liposomal and albumin delivery systems have been employed for intravenous administration of several hydrophobic drugs.^{(Zamboni, 2005)(Li, Braiteh, & Kurzrock, 2005)} In cancer studies, Li et al. investigated the in vitro and in vivo anti-tumor activity of liposomal curcumin against human pancreatic carcinoma cells and demonstrated that liposomal curcumin inhibits pancreatic carcinoma growth and, in addition, exhibits antiangiogenic effects. ^{(Li, Braiteh, & Kurzrock, 2005)} Liposomal curcumin suppressed the pancreatic carcinoma growth in murine xenograft models and inhibited tumor angiogenesis. In the in vivo part of this study, the effect of liposomal curcumin was evaluated in comparison to untreated and liposomal vehicle treated mice. Comparison of effect of liposomal curcumin with free curcumin and biodistribution profiles of liposomal curcumin over free curcumin have yet to be evaluated to confirm the enhancement of curcumin bioavailability by liposomal curcumin. ^{(Anand, Kunnumakkara, Newman, & Aggarwal, 2007)} In the literature, there are a few reports on the binding of curcumin to liposomes and albumins using spectroscopic methods.^{(Kunwar, Barik, Pandey, & Priyadarsini, 2006)}

In an aqueous environment, such as the human gastrointestinal tract, curcuminoids are only sparingly soluble. Poor water solubility and limited gastrointestinal absorption are two interrelated issues that made it difficult in early research attempts to determine curcuminoids’ bioavailability.^{(Anand, Kunnumakkara, Newman, & Aggarwal, 2007)(Douglass & Clouatre, 2015)} Interestingly, turmeric-consuming cultures appear to have been long aware of at least one solution to this problem. In both culinary and Ayurvedic practice in South Asia, powdered turmeric is often combined with a source of fat, such as ghee, milk, or coconut milk. For example hot turmeric milk, or haldi ka doodh, is commonly recommended as a beneficial home remedy. As explained above, implicit in this cultural wisdom is that fat facilitates the absorption of curcuminoids from the gut.^{(Douglass & Clouatre, 2015)} Based on this evidence, appropriate delivery systems for medicinal curcumin products should be considered.

4. Potency of Curcumin

Many manufacturers of curcumin supplements aim to enhance and bioavailability of curcumin with the most potency in order to gain the maximum health benefits. Most supplements are made with curcumin with at least one additional ingredient to support curcumin absorption into the body.^{(Which Curcumin Supplement Has The Best Absorption?, 2017)} The main six ingredients used in most trade marketed supplements is discussed below:

95% standardized curcumin, is an extract derived from turmeric standardized to 95% purity of curcuminoids, with about 80% curcumin, about 10% – 20% DMC, and < 5% BMDC.^{(Hsu & Cheng, 2007)(Weisberg, Leibel, & Tortoriello, 2008)} The majority of curcumin supplements include this form of curcumin, often blended with piperine to enhance absorption. Using a standardized form of curcumin is important in order to gain the maximum health benefits; non-standardized forms are turmeric root extracts with an unknown amount of the beneficial element curcumin.

Bioperine, first patented by Sabinsa, is a standardized piperine composition derived from black pepper extract. It contains 95% piperine and is patented for its ability to increase the bioavailability of nutritional compounds. As described in Section 3.3.1, it has been shown to increase the bioavailability of curcumin and is therefore used in many nutritional supplements of curcumin.^{(BioPerine®, 2017)}

Longvida is a patented standardized solid lipid curcumin particle preparation and is composed of 20% curcumin and 80% phospholipids.^{(Nahar, Slitt, & Seeram, 2015) (Which Curcumin Supplement Has The Best Absorption?, 2017)}  The encapsulation of curcumin in lipids allows the curcumin to reach the gastrointestinal tract and be absorbed more effectively into the bloodstream, without being degraded by stomach acids.^{(Nootriment , 2017) (Nahar, Slitt, & Seeram, 2015)} A recent pharmacokinetic study in humans has shown an increased bioavailability of curcumin as compared to generic curcumin extract without any supporting adjuvants. ^{(Nahar, Slitt, & Seeram, 2015)} Moreover, the particles are shown to cross the blood-brain barrier, making it a promising preventative agent against neurodegenerative diseases.^{(Which Curcumin Supplement Has The Best Absorption?, 2017)}

Theracurmin is a form of curcumin nanoparticle. The productis a combination of 10% curcumin, 2% other curcuminoids (desmethoxycurcumin and bis-desmethoxycurcumin), glycerin, gum ghatti and water.^{(Sasaki, et al., 2011) (Douglass & Clouatre, 2015)} Absorption is increased by the water-soluble nanotechnology-based curcumin; in human studies showed a 30-fold increase of bioavailability as compared to conventional curcumin.^{(Sasaki, et al., 2011)}

Meriva is composed of 20% – 30% curcuminiods (of which about 80% is curcumin) and 80% soy-derived phospholipids; a combination that is also patented to increase bioavailability, similar to Longvida.^{(Which Curcumin Supplement Has The Best Absorption?, 2017)(Cuomo, et al., 2011) (Douglass & Clouatre, 2015)} Research studies have shown a 29-fold increase in absorption of total curcumiods in patients who were administered Meriva as compared to those who were given an unformulated curcumin mixture.^{(Cuomo, et al., 2011)}

BCM-95 (also known as Biocurcumin) combines micronized (i.e. particle-size controlled) curcumin with other turmeric compounds to improve the absorption of curcumin.^{(Douglass & Clouatre, 2015)} It is composed of 86% curcuminiods, including curcumin, DMC and BDMC, and 7-9% essential oils naturally present in turmeric. ^{(Which Curcumin Supplement Has The Best Absorption?, 2017)} It is therefore claimed to be a 100% turmeric product with superior bioavailability than curcumin alone. Research has shown that the patented product BCM-95 had an about 7-fold increased bioavailability as compared to a curcumin-lecithin-piperine formula.^{(Antony, Merina, Iyer, Judy, Lennertz, & Joyal, 2008)}

The most often used formulation is 95% standardized curcumin with piperine, because it was one of the first curcumin extracts available for manufacturers and the enhancing effects of piperine to increase bioavailability is well supported by scientific research. Newly developed curcumin products with enhanced bioavailability through the use of modern manufacturing technology also show beneficial effects for human health; however, their superiority over the 95% curcumin + piperine formulation is unclear, because most studies assessing these new products administer only curcumin extracts for the reference group without the use of piperine as an enhancing adjuvant – a comparator that is unmistakably inferior to a formulation that we already know works: 95% curcumin with piperine. Positive results from those studies may therefore appear artificially higher than they really are; thus conclusions can be misleading. Therefore, there is a need for more research comparing the effects of the different curcumin products, using a curcumin and piperine blend as the reference comparator. Until then, based on literature currently available, there is enough evidence supporting the claim that dietary supplements containing 95% standardized and piperine is one of the best formulations on the market today.