The Curcumin Conundrum

By Dr. Douglas Lobay, BSc, ND

Subscription button: Image of sunrise over a calm bay, with anchored boats.

“Hi, this is Dr. S from Vancouver. I just wanted to talk to you about a new curcumin compound that you might be interested in.”

“Ok.”

“Did you know that regular curcumin is a mixture of three different curcuminoids, namely diferuloylmethane, demethoxycurcumin, and bisdemethoxycurcumin.

“Yes, I think I remember that.”

“Regular curcumin is 60 to 75% diferuloylmethane, 10 to 20% demethoxycurcumin and less than 10% bisdemethoxycurcumin.”

“Aha?”

“And a lot of times the bisdemthoxycurcumin is only 1%.”

“Well, I have a new curcumin compound that is 30% bisdemethoxycurcumin.”

“Great?”

“A lot of new studies say it is better for inflammation and cancer than the old curcumin. I will email you some information and references about this new exciting product.  And if you’re interested….”

After the phone call I looked at my dispensary and pondered my perplexing dilemma.  I had four or five different turmeric and curcumin products sitting on my shelves.  One product was a mixture of turmeric powder, MSM, glucosamine, Boswellia, and ginger. Another product was listed as pure 95% curcuminoids. Another product was a mixture of 95% curcumin and a black pepper extract called bioperine. One product was a mixture of curcumin and phosphatidylcholine.  Yet another was a colloid mixture of curcumin with vegetable glycerin and ghatti gum. The dose of curcumin ranged from 55 to 500 millgrams per capsule or tablet.

I realized I had a conundrum on my hands.  I have been happily prescribing turmeric and curcumin products mainly for pain and inflammation and for adjunctive cancer treatment.  My recommendations were based on what little knowledge I had about curcumin and patient feedback.  I concluded that my recommendations were largely based on conjecture and inference on what information the supplement companies were providing about their products. So I decided to research a little further on the medical databases available and to see what I could learn.  I remembered that one tenet of naturopathic medicine is that the doctor should be a teacher.  I surmised that I should be able to convey accurate, practical, and useful information to my patients so they can make better choices about turmeric and curcumin.

Turmeric (Curcuma longa) is a perennial herb that is indigenous to India and Southeast Asia. It grows up to one meter in height.  It has small elliptical or oblong green leaves and a deep orange or yellow colored root or rhizome.  It is a member of the ginger or Zingiberaceae family and the Curcuma genus, along with over 100 allied species.  The brightly colored root and rhizome has been used as a culinary spice in food preparation.  As a part of curry powder, it has been mixed with coriander, cumin, black pepper, ginger, and other spices.  As a dye it has been used in the clothing and textiles industry. It has also been used in cosmetics and the food and beverage industry. The root and rhizome has been described as pungent, bitter, and earthy and has been used in Ayurvedic medicine for several thousand years.

The chemical constituents of turmeric have been identified as follows: 1% to 6% curcumin, 3% to 7% volatile oils, 2 to 7% fiber, 3 to 7% mineral matter, 6 to 8% protein, 5 to 10% fat, 6 to 13% moisture and 60 to 70% carbohydrate. Other sources have listed curcumin content from 1 to 8%.  It should be noted that the total curcumin content of the root is probably better referred to as total curcuminoid content. The curcuminoid content reflects the fact that there are several slightly different but related chemicals in the root and rhizome of turmeric.1

Curcumin is the name given to the chemical that is responsible for the bright yellow and orange color of the turmeric plant in the root and rhizome. Curcumin has been identified as the main active ingredient of this plant. However, three main curcuminoid molecules have been identified in the turmeric plant: Curcumin or diferuloylmethane, demethoxycurcumin and bisdemethoxycurcumin. The naturally occurring content of curcumin has been identified to be between 60 to 70% while demethoxycurcumin is between 20 to 27% and bisdemethoxycurcurcumin is between 10% and 15%.1

Turmeric and curcumin have demonstrated a wide range of activity including anti-inflammatory, anti-HIV, antibacterial, antifungal, nematocidal, antiparasitic, antimutagenic, antidiabetic, antifibrinogenic, radioprotective, wound healing, lipid lowering, antispasmodic, antioxidant, immunomodulatory, anticarcinogenic, anti-Alzheimer’s, and other effects. Another paper explained that the data indicated that curcumin has demonstrated better anti-cancer effects, demethoxycurcumin showed better antilipemic activity and bisdemethoxycurcumin showed better bile and growth inhibition.1,2

Curcumin has been described as a pleiotropic molecule with a multiplicity of different and unique biochemical effects. Some of effects include down-regulation of nuclear factor kappa-beta (NF-KB), decreased transcription-3 transductase and activator Wn/beta catenin, and increased peroxisome proliferator receptor gamma and Nrt2 cell signaling pathways, which decrease adipokines, including tumor necrosis factor (TNF), interleukin-6, resistin, leptin, and monocyte chemo-tactic protein-1 and increase adiponectin and other gene products. Curcumin modulates cell survival proteins, histone acetylase, histone deacetylase, protein kinases, protein reductases, glyoxalase I, proteasome, human immune deficiency virus I (HIV1), integrase, HIV proteins, Fts Z protofilaments, carrier proteins, DNA, RNA and metal ions. In light of the complex and varied effects, curcumin has been described as a strong cell signaling molecule. Curcumin inhibits several signaling pathways at multiple levels with effects on cellular enzymes, such as cyclooxygenase and glutathione s-transferase, immunomodulation, and on angiogenesis and cell adhesion. Curcumin was further shown to affect gene transcription and induce apoptosis in preclinical studies.3,4,5

Several other non-curcumin chemical constituents of turmeric have been identified and have exhibited antioxidant, anti-inflammatory and anti-cancer effects.  These include turmerin, tumerone, elemene, furanodiene, cardione, biscurarone, cyclocurcumin, calebin A, and germacrone. Other volatile oil fractions include tumerone, altantone, and zingiberone.6,7

Curcumin has a notoriously poor absorption profile. Low plasma and tissue levels are due to poor absorption, rapid metabolism, and rapid systemic elimination. Curcumin has been demonstrated to show absorption through active transport mechanism across the small intestine. Curcumin and bisdemethoxycurcumin show concentration-dependent inhibition through active transport, while demethoxycurcumin shows a carrier-mediated saturation pathway.2,8

In rats a dose of 1000 mg/kg of curcumin was found to produce a plasma level of an average of 15 ng/ml reflecting a relative absorption rate of approximately 1%. In humans, curcumin levels were measured to be an average of 11.1 nmol/l or 6 ng/ml one hour after consuming between 4 to 8 grams of curcumin. In another study in humans, consumption of 2 grams of curcumin alone made a very low or undetectable measurement in blood levels.  Other reviews show a transient detection in plasma not exceeding 10 nanograms/ml after a single dose of varying strengths of curcumin. Another study shows a blood level ranging from 0.42 to 1.75 micromoles/l after one hour of consuming 4 to 8 grams of curcumin, while a level of 0.01 micromoles/l was noted after consuming 3.6 grams of curcumin.1,3,9,10

To enhance and improve absorption curcumin has been mixed with a variety of compounds, including liposomes, B-lactoglobulin, phospholipid complex, polymer encapsulation, PEG-PEI encapsulation, oil body encapsulation, soy protein isolate, bovine serum globulin, curcumin polymers, hydrogels, hyaluronic acid, organic gel-based nanoemulsions, casein, nano-particles, gold nano-particles, PHEMA nanoparticles, silica nanoparticles, GMO nanoparticles, chitosan nanoparticles, cyclodextrin nanoparticles and other novel chemicals. Other formulations have mixed curcumin with black pepper or a black pepper extract called piperine.3,8,11

One study compared the absorption of curcumin, demethoxycurcumin, and bidemethoxycurcumin and its metabolite tetrahydrocurcumin after oral absorption of three different curcumin formulations.  One product of curcumin mixed with cellulose and natural antioxidants enhanced absorption by 45.9 times. A second product of curcumin mixed with volatile oils enhanced absorption by 34.9 times. And a third product of curcumin mixed with a phytosome enhanced absorption by 5.8 times. Bioperine is believed to inhibit intestinal and hepatic degradation of curcumin by decreasing cytochrome activity and inhibiting glucuronidation and sulfation, which has been shown to increase curcumin levels by 20 times. Adding 20 milligrams of piperine increased levels of curcumin by 20 times at one-hour post-consumption. Improved solubility, stability, and low first pass metabolism have dramatically improved curcumin absorption of up to 100 times compared to unformulated curcumin.3,11-14

While limited systemic bioavailablity has hindered the use of curcumin as a potential therapeutic agent, thousands of studies have demonstrated therapeutic efficacy of curcumin at low doses. Some researchers contend that in view of the overwhelming body of compelling data, it is very possible that curcumin bioavailability may actually not even be a serious issue. Numerous reports suggest that bioavailability could not be a concern. The dose of curcumin recommended varies from as low as 10 milligrams/day of curcumin powder and 80 milligrams/day of curcumin liquid to as high as 12 grams of curcumin per day. Some researchers have concluded that even relatively low doses of curcumin can have clinical benefits. A commonly recommended dose of curcumin appears to be between 500 to 2000 milligrams per day for general anti-inflammatory effects.3,13-15

Curcumin is believed to be safe for human consumption in doses up to 12 grams of curcumin per day. Reported side effects of curcumin consumption include gas, bloating, indigestion, heartburn, upset stomach, diarrhea, headache, and in some cases skin rash. Its use during pregnancy and lactation has not been determined and is not recommended. In vitro studies show that curcumin can inhibit platelet aggregation and its use with patients who are consuming blood thinners and anticoagulant drugs is cautioned.  Its concurrent use with cancer patients who are receiving chemotherapeutic drugs is also cautioned.  Some preliminary studies show that it can help promote the benefits of chemo drugs while having negligible side effects. However, its use with patients who are receiving chemo drugs should be evaluated and recommended on an individual basis.1,8,9

One paper listed the half-life of curcumin as five minutes. Another paper has measured detectable curcumin in plasma six to seven hours after oral consumption.  Most researchers generally agree that curcumin is rapidly degraded by phase 1 and phase 2 pathways in the liver and small intestine, particularly by glucuronidation and sulfation. Approximately 75% of curcumin and its byproducts is recovered in stool and less than 25% recovered in urine. Metabolic degradation products of curcumin include ferulic acid, vanillin, betahydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin and other dimerized end products and have been detected in plasma samples within 30 minutes after oral consumption of curcumin. Some researchers have suggested that the metabolic byproducts of curcumin are biologically active as well and account for the benefits of curcumin in spite of the fact it has notoriously poor absorption, rapid degradation, and elimination.  Curcumin and its byproducts have been detected in fecal material 3 to 12 days after oral consumption.1,9,15-19

The Linus Pauling Institute in Oregon has published an overview of the research of the medical benefits of curcumin. The authors point out that the mounting evidence of preclinical studies shows that curcumin modulates numerous molecular targets and exerts antioxidant, anti-inflammatory, anticancer and neuroprotective activities.  They further elaborate that while a few preliminary studies show that curcumin has anti-inflammatory activity in humans, larger randomized controlled trials are needed to establish its efficacy in osteoarthritis and radiation-induced dermatitis. They continue to report that no substantial evidence exists so far that curcumin improves cognitive performance in older adults with or without cognitive impairment.  Also, its use for depression is very preliminary and long-term clinical trials are recommended.  The use of curcumin by patients with diabetes is also preliminary and more long-term trials are needed.  And while in vitro testing of curcumin in cancer activity remains encouraging, human trials are very limited particularly in patients with breast, prostate, pancreatic, colorectal, lung, and skin cancer. Other benefits of curcumin have been reported for cardiovascular disease, dermatology, and ophthalmology and while encouraging, the authors conclude that further investigation is warranted.9,20-23

The anti-inflammatory benefits of curcumin are particularly encouraging. Curcumin has been observed to down regulate nuclear factor kappa beta, which is an important signaling molecular for multiple pathways that promote inflammation. In one study, 1.2 grams of curcumin was consumed for 5 days after inguinal repair surgery and showed that curcumin was comparable to 300 milligrams/day of phenylbutazone.  In another study of 18 patients with rheumatoid arthritis showed that consumption of 1.2 grams of curcumin per day for two weeks significantly improved morning stiffness, walking time, and joint swelling. In yet another study, 45 patients with rheumatoid arthritis who consumed 0.5 grams of curcumin per day for eight weeks showed it to be just as effective as 50 milligrams per day of diclofenac.3,18,24

So why the conundrum?  Turmeric has been consumed in foods by cultures around the word and used in folk medicine for thousands of years.  Reported antioxidant, anti-inflammatory, anticancer effects have been observed in the scientific literature.  Curcumin has been identified as the main active ingredient believed to be responsible for its purported medicinal effects.  Curcumin has poor absorption, rapid degradation and relatively fast elimination. Novel ways of enhancing curcumin absorption and preventing its breakdown and elimination have been invented. Several other constituents of turmeric have also been identified to have biological activity besides curcumin. The use of turmeric as a functional food in our diet is recommended for its potential health benefits.  The use of curcuminoid extracts for its anti-inflammatory effects appears to be reasonable and beneficial.  The use of curcuminoid extracts in cancer and other conditions is preliminary at best and more research is needed to substantiate these health benefits.  The dose of curcumin varies widely throughout the scientific literature and no standardized recommendation has been firmly established.  Daily doses between 10 milligrams to 12 grams per day have been reported on various medical databases.  A reasonable recommendation of curcumin can vary from 500 milligrams to 2000 milligrams per day.  Higher doses can be consumed if desired or recommended.  The development of novel curcumin products such as nanoparticles or mixed with black pepper extracts, phospholipids or other emulsions is exciting.  The dosage of these products is variable and best based on the available absorption profile data presented by the research or the manufacturer.

So, in conclusion, I will continue to recommend turmeric and curcumin products in my clinical practice to patients with various health problems, but particularly those with acute and chronic inflammation.  I will experiment with different products and formulations and use my clinical experience and listen to patient feedback.  I will try to read the medical databases and keep up to date with scientific research as it evolves with this exciting functional food and natural medicine.

References

  1. Nelson KM et al. The Essential Medicinal Chemistry of Curcumin. J Med Chem. 2017 Mar 9; 60 (5): 1620-1637.
  2. Wang YH et al. Absorption mechanism of three curcumin constituents through in situ intestinal perfusion method. Bra J Med Biol. 2017 Sep: 50(11): e 6353.
  3. Prasad S et al. Recent Development in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: The Golden Pigment from Golden Spice. Cancer Res Treat. 2014 Jan; 46(1): 2-18.
  4. Hewlings SJ and Kalmam DS. Curcumin: A Review if Its’ Effectiveness in Human Health. Foods. 2017; Oct; 6(10): 92.36.
  5. Gupta C et al. Therapeutic roles of curcumin lessons learned from clinical trials. AAPS J. 2013. Jan; 15(1); 195-218.
  6. Aggarwal BB et al. Curcumin-free turmeric exhibits anti-inflammatory and anti-cancer activities: Identification of novel components of turmeric. Mol Nutr Food Res. 2013 Sep; 57(9): 1529-1542.
  7. Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa, a review of preclinical and clinical research. Altern Med Rev. 2009 June; 14(2): 141-153.
  8. Anand P et al. Bioavailability of Curcumin: problems and promises. Mol Pharma. 2007 Nov-Dec; 4(6): 8-7-18.
  9. Higdon J et al. Curcumin. Linus Pauling Institute. Oregon State University Micronutrients Information Center. www.lpi.oregonstate.edu/mic.dietary-factors/phytochemicals/curcumin. 2005 update 2016.
  10. Padamanaban G, Nagurj VA. Curcumin May Defy Medicinal Chemists. ACS Med Chem Lett. 2017; 8(3): 274-279.
  11. Jamwal R. Bioavailable curcumin formulations: A review of pharmokinetic studies in healthy volunteers. J Integr Med. 2018 Nov; 16(6): 367-374.
  12. Jager R et al. Comparative absorption of curcumin formulations. Nutr J. 2014; 13: 11.
  13. Schiborr C et al. The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy human and differs between the sexes. Mol Nutr Food Res. 204 Mar; 58(3): 516-527.
  14. Jamwal R. Bioavailable curcumin formulations: A review of pharmokinetic studies in healthy volunteers. J Intergr Med. 2018 Nov; 16(6): 367-374.
  15. Toden S and Goel A. The Holy Grail of Curcumin and Its Efficacy in Various Diseases: Is Bioavailability Truly a Big Concern. J of Restorative Medicine. Nov/Dec 2017. 6(10): 27-36.
  16. Sharma RA et al. Pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol. 2007; 595; 453-470.
  17. Sharma RA et al. Curcumin: the story so far. Eur J Cancer. 2005 Sep. 41(13): 1955-1968.
  18. Daily JW et al. Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Med Food. 2016 Aug. 19(8): 717-729.
  19. Ravindrnath V and Chanrdsenkhara N. Metabolism of curcumin—studies with (3H) curcumin. Toxicology. 1981-82; 22(4):33-44.
  20. Pescosolido N et al. Curcumin: therapeutic potential in ophthalmology. Planta Med. 2014 Mar: 80(4): 249-254.
  21. Wongcharoen W et al. Effects of curcuminoids on frequency of acute myocardial infarction after coronary bypass grafting. Am J Cardiol. 2012 Jul 1; 110(1): 40-44.
  22. Qin S et al. Efficacy and safety of turmeric and curcumin in lowering lipid levels in patients with cardiovascular risk factors: a meta-analysis of randomized controlled trials. Nutr J. 2017 Oct. 16: 68.
  23. Vaughn A et al. Effects of Turmeric (Curcuma longa) on Skin Health: A systematic Review of Clinical Evidence. Phytotherapy Research. May 2016; 30(8): 1243-1264.
  24. Nelson KM et al. Curcumin May (Not) Defy Science. ACS Med Chem Lett. 2017 May 11; 8(5): 467-470.