June 23, 2019

Curcumin: Uses, Benefits, and Properties Explained

Curcumin is the most bioactive substance in turmeric, with a wide variety of benefits such as antioxidant, anti-tumor, metal toxicity, neuroprotection, kidney, liver, and heart health, gut inflammation, and more. Curcumin by itself has very poor bioavailability when consumed, in this article we outline different methods to enhance bioavailability, explaining how, and which method gives the best result for delivering the most effective curcumin.

FIGURE 1: The many benefits of curcumin displayed in humans⁰

Curcumin and Bioavailability

Turmeric has been used as a spice and for medicinal treatment for over 4000 years in India for treatment of arthritis, gastrointestinal discomfort, and as an anti-inflammatory agent¹. Turmeric contains only 2-5% of curcumin by weight, so consuming turmeric or a powdered turmeric supplement in order to benefit from the effects of curcumin is an ineffective strategy.

In the present day, curcumin is extracted from turmeric to obtain a more purified source of curcumin. Typically a curcumin extract is standardized to contain no less than 95% curcuminoids. The curcuminoids are a family of three compounds – Curcumin, Demethoxycurcumin, and Bisdemethoxycurcumin.

Curcumin is the most abundant of these curcuminoids, composing of roughly 77% of the total curcuminoids, with demethoxycurcumin comprising about 17%, and bisdemethoxycurcumin comprising about 6%.

FIGURE 2: The molecular structures of the curcuminoids²

Simply taking a curcumin extract supplement will not provide any benefits, with one human study demonstrating a dose of 2 grams taken not leading to any elevation in serum levels, meaning the amount of curcumin actually absorbed was very small, if anything at all. One easy way to significantly improve its bioavailability is to consume it with black pepper extract, otherwise known as piperine. The combination of pairing curcumin with piperine is well researched, and has been shown to increase bioavailability of curcumin by up to 20-fold³. This coadministration with piperine also lead to a decrease in the rate of elimination and clearance. This effect on increased absorption with piperine is seen due to piperine’s ability to inhibit the activity of the enzyme CYP3A4, the major enzyme responsible for Phase I drug metabolism; which in this case would lead to the reduction of the 4 double bonds in curcumin⁴, leading to formation of reduced curcuminoids such as tetrahydrocurcumin, which will be discussed further below.

Curcumin also has improved bioavailability when paired with the flavonoid Quercetin, due to quercetin’s ability to inhibit the P-glycoprotein efflux pump in the intestine. Combinations of curcumin with piperine and quercetin have been employed successfully for the bioenhancement of curcumin⁰.

Another way to increase bioavailability of curcumin extract is to consume it with a high fat meal, which will slow the transit time in the gastrointestinal tract and improve the absorption. One study showed this effect to lead to a 29-fold increase in absorption compared to curcumin extract alone⁵. However, it is important to note that even with the 29-fold increase, plasma concentration of curcumin was still not enough to see the anti-inflammatory benefits of curcumin.

Although combining a curcumin extract with either piperine or dietary fats led to 20-29-fold increases in bioavailability, it was still not enough to reap the benefits of curcumin.

Micronizing curcumin increases the surface area of the particles, thus leading to improved water solubility and increasing bioavailability, this method changes the actual type of curcumin being ingested, so its bioavailability can further be increased by piperine. Micronized curcumin taken by itself showed a 14-fold increase in bioavailability compared to curcumin alone⁶.

The most effective methods for increasing bioavailability have been shown to be nanosuspensions and carrier based nanosystems. Methods such as placing curcumin in a cyclodextrin complex exist, and in doing so are able to significantly enhance the water solubility and bioavailability of curcumin⁷.

Nanoparticle Based Delivery Systems

Transporting nanoparticles of curcumin through the gastrointestinal mucosa (mucous membrane of the stomach) permits significant bio-enhancement. There are several different nano-based delivery systems which can be used for curcumin, such as liposomes, solid lipid nanoparticles, micelles, and microemulsions

Curcumin and different delivery systems for imrpoved bioavailability

FIGURE 3: Various nanoparticle formulations used to increase bioavailability of curcumin⁰

Although these delivery systems differ in the way they are produced and their effectiveness, their goal is the same: to reduce the particle size of curcumin, and to increase lipophilicity of the curcumin in order for it to be absorbed through the intestinal lymphatic system⁸.

Microemulsions

Microemulsions of curcumin can be formed by mixing oil, water, and surfactants with the curcumin. These microemulsions show a 22.6-fold increase in bioavailability compared to curcumin suspension⁹.

Liposomes and Micelles

Liposomes differ from Solid lipid nanoparticles and micelles because they have the ability to encapsulate and deliver water soluble drugs or supplements, as well as fat soluble products like curcumin. Liposomes have an outer fat soluble shell and a water soluble core, and can be layered like an onion with alternating fat and water soluble layers, the more layers the liposome has, the larger it is (some are over 1000 nm), and the less of a suitable drug delivery system it becomes. Due to their generally larger size compared to micelles, they are not as effective in delivering a fat soluble product like curcumin. This can be shown in studies comparing the bioavailabilities of liposomes vs micelles, where curcumin micelles demonstrated a 117-fold increase in bioavailability ^10,compared to a curcumin extract. Studies done on liposomal curcumin demonstrated only a 7.8-fold increase in bioavailability compared to curcumin suspension⁰.

Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) are a new pharmaceutical delivery system with a solid lipid core. SLNs of curcumin have been formulated being only 20-80nm in size¹¹. SLNs are different than micelles in the fact that they are solid lipids at body temperature compared to being oils, with a surfactant coating on the outside making them more stable than liposomes or microemulsions¹² This difference makes SLN based curcumins the most potent and bioavailable form of curcumin to date, with up to 155-fold increases in bioavailability being documented in clinical studies, SLN curcumin edges out micellar curcumin in superior bioavailability, as the difference in their nanostructures would indicate¹³.

SLN compounds are able to have prolonged blood circulation, as well as the unique ability to permeate the blood brain barrier, resulting in improved brain delivery compared to other nutraceutical delivery systems¹⁶.

SLN Curcumin can be applied as a topical gel, and is able to permeate the skin for pigmentation and dermatitis treatments¹⁴.

Even though they are lipid based, SLN curcumin formulations are able to mix well in water due to their small particle size.

One example of a SLN curcumin formulation is Longvida® Optimized Curcumin, which is also the only form of curcumin that has been shown in clinical studies to cross the blood-brain barrier, and a daily dose of 400mg shows notable improvements in brain function after just one hour¹⁵. Evidence shows that Longvida can be up to 285x more bioavailable and 7 times longer lasting than a standard curcumin extract⁶. Leviathan Nutrition’s overall health product – IRE has 750mg of Longvida® Optimized Curcumin per serving, meaning that even with half a serving per day, users will still be getting a clinically effective dose.

Molecular Structure of Curcumin

Curcumin’s numerous benefits can be attributed to its unique molecular structure. The structure of curcumin is the result of two structures of ferulic acid being joined together by a methylene bridge.

Figure 4: Fuleric Acid

Curcumin has three important aspects of its structure which are responsible for the majority of its benefits: an aromatic o-methoxy phenolic group, α, β-unsaturated β-diketo moiety, a seven carbon linker with a methylene group (the only fully saturated carbon on curcumin’s main structure)¹⁷. In order to understand these portions of the structure of curcumin, please see the diagram below

FIGURE 5: The structure of curcumin is broken down into: Aromatic o-methoxy phenolic groups (1), α, β-unsaturated β-diketo moiety (2), a seven carbon linker (3) with a methylene group (4, arrow), and two negatively charged oxygens to bind to toxic metals (5)

The two o-methoxyphenol groups on each side of the molecule, as well as the methylene carbon in the middle of the structure contribute to the antioxidant activity of curcumin, where electrons or hydrogen atoms are donated to reactive oxygen species. The unique ability for the β-diketo moiety to undergo a process known as keto-enol tautomerism, along with the long chain of carbons linking curcumin together both assist in curcumin’s ability to form covalent or hydrogen bonds to a large number of molecules in the human body, such as enzymes, carrier proteins, inflammatory molecules, DNA, and RNA

FIGURE 6: The molecular targets of curcumin¹⁹

The two carbonyl oxygens can bind metals (known as chelation), giving curcumin its ability to remove toxic heavy metals such as arsenic, lead, and mercury from the body¹⁸. Each of these important functional groups can be modified to improve certain properties in the structure of curcumin, creating drugs known as synthetic analogs of curcumin, which are widely researched for their application in cancer treatment.

Synthetic Analogs of Curcumin

There are hundreds of different analogs of curcumin which have been synthesized in order to amplify the known properties of curcumin, two of the most popular analogs are known as EF24 and HO-3867.

FIGURE 7: The synthetic analogs EF24 (Top) and HO-3867 (Bottom) of curcumin developed as cancer treatment drugs

In these compounds, the aromatic rings are substituted with Fluorine atoms to give stronger electrostatic interactions than the parent compound, as well as the center of the molecule now having a hydrogen for donation attached to a nitrogen or oxygen as opposed to the methylene carbon that curcumin is known for. These adjustments in the structure lead to greatly increased bioavailability, anti-inflammatory, and anti-cancer effects²⁰. To demonstrate these effects, EF24 has been shown to be 10 times more effective, and less toxic than the anticancer drug cisplatin²¹

Since these compounds have been chemically altered and do not occur in nature, they are only available as drugs and are not allowed to be sold as dietary supplements.

Tetrahydrocurcumin and other Reduced Forms

Another class of notable compounds derived from curcumin (and the curcuminoids) are tetrahydrocurcumin (and the tetrahydrocurcuminoids). Unlike the synthetic analogs of curcumin, these tetrahydrocurcuminoids are available as dietary supplements, since they are a direct result of the metabolism of curcumin itself, these compounds are simply the curcuminoid structures with the two double bonds reduced on the seven carbon linker.

FIGURE 8: The structures of curcumin and tetrahydrocurcumin - the reduced form of curcumin

Tetrahydrocurcumin is white in color, which makes it a popular choice for lotions compared to the yellow-colored curcumin. Tetrahydrocurcumin is 3 times more bioavailable than curcumin, and has stronger anti-oxidant effects than curcumin. On the contrary, tetrahydrocurcumin lacks anti-inflammatory and pro-oxidant activities. Curcumin is also able to bind to more molecules in the body, including DNA, while Tetrahydrocurcumin cannot. The targets of curcumin vs tetrahydrocurcumin are summarized in the following figure:

FIGURE 9: Differences in target effectiveness of curcumin vs tetrahydrocurcumin ²³

To summarize, Tetrahydrocurcumin has better anti-oxidant effects and bioavailability, as well as its white color being useful in its application in lotions and creams, but the anti-inflammatory, pro-oxidant, and its ability to bind to many targets of curcumin make it a better, more versatile compound overall.

Curcumin Metabolism Explained

Understanding the metabolism of curcumin in the body gives us a clear understanding for the poor bioavailability of curcumin. Curcumin is mostly metabolized in the liver. Curcumin is metabolized by Phase I and Phase II drug metabolism, where it either gets reduced or converted to curcumin glucuronide and curcumin sulfate. These two metabolites are a result of Phase II metabolism, and are inactive metabolites.

FIGURE 10: The Phase II metabolites of curcumin: Curcumin glucuronide (II) and Curcumin Sulfate (III)²³

However, some of the reduced metabolites of curcumin as a result of Phase I metabolism, such as tetrahydrocurcumin which was discussed above, do have some active properties.

There are some methods to improve this metabolism, the first and most effective method is by encapsulating the curcumin molecule in a lipid soluble nanocarrier, such as a liposome, micelle, or solid-lipid nanoparticle, with the latter showing the greatest stability and effectiveness. Doing this to the curcumin makes it fat-soluble enough to be absorbed through the lymphatic system and enter systemic circulation where it is now active. Being absorbed by the lymphatic system will bypass metabolism through the liver entirely, resulting in none of the curcumin being degraded into curcumin glucuronide, sulfate, or other reduced forms.

Another method of improving the bioavailability of curcumin is by adding piperine. The reason why this enhances bioavailability is because piperine can inhibit the activity of the enzyme CYP3A4 as well as glucuronidation, which will slow down the phase I metabolism and the amount of curcumin converted to inactive metabolites.

In drug metabolism, the P-glycoprotein efflux pump is responsible for transporting certain compounds out of the membrane to be excreted from the body.²⁵ The addition of Quercetin, which has been shown to inhibit activity of P-glycoprotein, can further improve the bioavailability of curcumin if it is being metabolized by the liver²⁶.

However, with the methods above regarding piperine and quercetin, it is important to note that this route still undergoes liver metabolism, so there is still some Phase I and II metabolism taking place as these methods are not completely able to inhibit metabolism.

Curcumin and the Heart

Curcumin exhibits cardiovascular protective effects due to its ability to protect against oxidative stress, apoptosis (cell death), inflammation, as well as its ability to decrease cholesterol²⁷. The effect of curcumin on the heart has been studied in situations involving: cardiac hypertrophy, heart failure, drug-induced cardiotoxicity, myocardial infarction, atherosclerosis, abdominal aortic aneurysm, stroke and diabetic cardiovascular complications²⁸

Curcumin preserves cardiac function and promotes proper cardiac muscle tissue repair after heart attack²⁹

Curcumin has been shown to prevent and reverse cardiac hypertrophy (enlarged heart)³⁰. This particular effect of curcumin can prove to be useful in athletes such as bodybuilders, who use compounds that contribute to an enlarged heart, which becomes a major health issue in these athletes later on in life.

Patients taking 150mg of a standardized curcumin supplement twice per day experienced an improvement in endothelial dysfunction (a condition where the lining of the arteries fails to function normally) that was comparable to atorvastatin, a statin prescription drug used to treat cholesterol.³¹

Curcumin and the Liver

Curcumin has demonstrated the ability to protect the liver by lowering enzyme values, lipid peroxidation, increasing activity of the master antioxidant glutathione, and other mechanisms after the liver was subjected to damage³².

Curcumin also protects the liver from damage from drinking alcohol, mainly by raising glutathione levels³³.

Curcumin and the Kidneys

Curcumin protects the kidneys in chronic kidney disease by reducing leakage of pro-inflammatory molecules through the intestine by increasing intestinal alkaline phosphatase, this prevents the ability of these pro-inflammatory molecules from entering the circulatory system³⁴.

Curcumin improved creatinine clearance, which is a main indicator of proper kidney function

The protective effects of curcumin on the kidneys has been thoroughly studied in cases involving: diabetic nephropathy, chronic renal failure, ischemia and reperfusion, and nephrotoxicity induced by toxic compounds³⁵

Curcumin and Cholesterol

Curcumin taken at a low dose has been shown to lower LDL cholesterol, overall cholesterol, as well as triglyceride values³⁶.

Curcumin may have significant effects on raising HDL cholesterol values if it is taken as a more bioavailable form than a typical curcumin extract³⁷

Curcumin and Digestion

Because it has higher bioavailability in the gastrointestinal tract compared to other organs, curcumin has been studied in diseases such as inflammatory bowel disease, colorectal cancer, and hepatic fibrosis³⁸.

Curcumin prevents gastrointestinal induced ulcers and can be used for ulcer treatment³⁹.

Curcumin displays pre-biotic like activity, resulting in positive changes in gut flora⁴⁰.

Curcumin and Joint Health

Curcumin has been shown to be a more effective anti-inflammatory than NSAIDs such as aspirin and ibuprofen⁴¹ and even demonstrated effects rivaling that of corticosteroid treatment without the side effects.⁴²

Curcumin has been shown to slow the disease progression of osteoarthritis, reduce pain, increase physical function, and quality of life in many clinical studies involving human patients⁴³.

Curcumin and the Brain

Curcumin can protect neurons and prevent cell death after spinal cord injury⁴⁴.

Curcumin is able to reduce the amount of water content in the brain after cerebral ischemia/reperfusion injury (when blood flow is restricted to the brain causing damage, and blood flow is then returned)⁴⁵.

Curcumin shows promise for treatment of brain cancers such as glioblastoma⁴⁶.

Curcumin is able to increase levels of the omega 3 fatty acid DHA in the brain⁴⁷, taking supplemental DHA itself is not able to increase DHA levels in the brain⁴⁸, making this a unique use for curcumin in humans.

Curcumin can also protect the brain against toxic effects caused by fluorine⁴⁹.

A highly bioavailable curcumin supplement also has nootropic effects, A dose of 400mg/day of Longvida® optimized curcumin resulted in a significant improvement in cognition and mood in as little as an hour in patients⁵⁰

Curcumin and Eye Health

As mentioned before, Water soluble curcumin cyclodextrin complexes used to make eyedrops showed great absorption for a once daily treatment for damaged retina⁵¹. Curcumin has been shown to be an effective treatment for dry eye disease⁵².
Curcumin can be used as a treatment for cataracts due to its ability to prevent the accumulation of free radicals⁵³.

Final Summary

To summarize all of the information given in this article, curcumin is one of the most effective nutraceuticals to exist, with a unique molecular structure giving it powerful properties as an anti-oxidant, anti-inflammatory, and the ability to remove heavy metals from the body. Previously, curcumin was not able to display these many health benefits in humans due to poor bioavailability. The innovation of nanotechnology has allowed more bioavailable forms of curcumin to be made and deliver the benefits of this nutraceutical to humans, with solid lipid nanoparticle systems such as Longvida® being the most effective (up to 285x more bioavailability and 7x longer lasting than curcumin extract), and micelle encapsulated forms of curcumin a close second. This is due to both formulations being absorbed through the lymphatic system bypassing liver metabolism. Consuming a curcumin extract with piperine or a high fat meal can increase bioavailability by 20x-30x, but is still not enough to see the anti-inflammatory effects of curcumin; which is why it is important to use a solid lipid nanoparticle or micellar curcumin formulation to reap the full benefits. Longvida® is the only form of curcumin to be able to cross into the blood brain barrier and enhance cognitive function immediately after taking it.

Curcumin has proven use in humans aiding in digestion, joint health, kidney, liver, heart, eye health, reducing cholesterol levels, and shows promise in cancer treatment. Curcumin is able to reduce the size of an enlarged heart, making it a promising supplement for athletes who have taken PEDs. Curcumin has stronger anti-inflammatory properties than NSAIDs, and also rivals some corticosteroids in effectiveness without the side effects. Synthetic analogs of curcumin are being made to provide effective cancer treatments. Some metabolites of curcumin, such as tetrahydrocurcumin, retain some of the effective properties of curcumin, but do not display many of curcumin’s other benefits. Pairing curcumin with other ingredients such as quercetin and resveratrol show enhanced effects and improved absorption of all of these ingredients.

In Leviathan Nutrition IRE, we pair Curcumin with piperine, resveratrol, and quercetin for high inhibition of CYP3A4 enzymes and P-glycoprotein efflux pump in the intestinal mucosa, leading to improved uptake of curcumin, as well as the other ingredients in our formula which have been clinically shown to have enhanced effectiveness when paired with piperine. Delivering 750mg of Longvida® Optimized Curcumin per serving, as well as 10 other clinically dosed nutraceuticals, we have formulated one of the most potent health supplements that cutting edge technology is able to offer.

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