Curcumin

Mary S. Easton UCLA Alzheimer Translation Center

 

What is curcumin?  

Curcumin, is an anti-inflammatory molecule in the turmeric root, a relative of ginger. Turmeric has been used for thousands of years as a medicinal preparation and a preservative and coloring agent in foods. Curcumin was isolated as the major yellow pigment in turmeric; chemically diferulomethane, and has a polyphenolic molecular structure similar to other plant pigments (eg. extracted from grapes in wine (resveratrol), or in green tea (catechins) or in certain fruit juices (blueberries, strawberries, pomegranates etc.) This polyphenols share in common anti-oxidant and anti-inflammatory properties with associated health benefits

Can eating turmeric-based curries, increase curcumin levels in the blood?

India has a low incidence and prevalance of Alzheimer's, which may be related to genetics or a particular intake of specific foods. Some people attribute the low incidence of Alzheimer's to a high intake of turmeric in Asia. As turmeric contains an average of 5-10% curcumin, the daily intake of curcumin is approximated in India is thought be about 125 mg. Importantly incooking curries, curcumin is often dissolved and extracted into fat, eg. ghee, which may increase its bioavailability. Animal studies have demonstrated that the way it is administered affects its distribution in the body. Unformulated curcumin, such as purified and dried curcumin in a capsule, is absorbed easily but the liver and GI tract tag it in a way that make it not very bioavailable to the brain. There is a lot of confusion about curcumin bioavailability versus absorption. Curcumin is absorbed, but not necessarily bioavailable. Further GI and liver glucuronidation or sulfation "tagged curcumin" which interfere with bioavailability it some tissues also leadds to its rapid removal by the kidneys. Unliked tagged curcumin, free curcumin readily crossed the blood brain barrier and is relatively stable.

To increase free curcumin and its half life, one company Sabinsa has used the strategy to reduce curcumin's clearance by inhibiting glucuronidation using piperine (Sabinsa C3 complex). Glucuronidation is a method to to rid the body of toxins and remove metabolized drugs. Therefore one should determine blood levels of currently used medications after taking this formulation for several days.

Other proposed strategies are to increase its solubility (Meriva), or to encapsulate and protect it from hydrolysis and to control where in the intestine it is absorbed (Longvida).

In summary curcumin is easily absorbed but not necessarily very bioavailable to the brain (such as dissolved in cooking oils or formulated). It is stable in fatty tissues such as the brain, but not in blood.

If I decide to take curcumin in capsule form, should I choose pure curcumin or a formulation?

There are many formulations on the market. If you decide to take curcumin for a disease peripheral to the brain such as arthritis, any formulation may suffice. There are two essential criteria to consider, first, is there evidence that the formulation will lead to adequate curcumin levels in the target tissue?, and second is the formulation manufactured by a company with Good Manufacturing Practice (GMP). Since curcumin is a metal chelator it can chelate toxic metals like lead in the ground. Sometimes it is difficult to determine if the manufacturer is a GMP company, because your are purchasing the product from the distributor, not the manufacturer. Several manufacturers claim superior absorption, but it is important to view the data used to make these conclusions. Typically these data show detection of increased glucuronidated (tagged for removal by the kidneys are limited penetration to the brain) but do not assess untagged curcumin, which is permeable to the brain. In other words,data demonstrating superior absorption as measured by liver-tagged curcumin poorly predicts levels achieved in the brain. In contrast, untagged or free curcumin readily penetrates the brain and free curcumin levels in the blood correlate positively with levels in the brain in animal studies. Dr. Frautschy received a National Institute of Health drug development grant U01AG028583 a Drug Development grant to develop a formulation of curcumin that can be taken orally and penetrate the brain. This led to development of a solid lipid particle formulation of curcumin patented by UC Regents and Veteran's Affairs and licensed to Verdure Sciences as Longvida. Each capsule is 500 mg (125 mg of curcumin). Verdure Sciences is certifed for Good Manufacturing Practice, ensuring the absence of toxic metals and using organically grown turmeric. DiSilvestro et.al., at Ohio State University found that the Longvida curcumin formulation reduced plasma levels of beta-amyloid as well as cholesterol and markers of inflammation in plasma of 40-60 year old subjects.

We are now conducting a clinical trial to determine Longvida's effects in subjects at risk for Alzheimer's.

 

How much curcumin should I take?

The short answer is 'we do not know the dose needed'. The answer to this question will also depend on how you take it, if you take it on an empty stomach, whether you dissolve it or not and whether and how it is formulated. Unlike drugs, one cannot determine the dose needed for curcumin unless one knows the tissue levels achieved for that formulation. Clinical trials for each each disease and each stage and each formulation would need to be conducted to identify effective tissue levels and that information will be needed to be able to recommend required dosing. In animals levels of 0.6 micromolar are sufficient to reduce amyloid pathology. If effective for prevention and treatment of MCI and Alzheimer's, the dose required may depend on stage. Extrapolation from animals studies suggest that a range of 4-8 capsules of 500 mg Longvida (125 mg of curcumin) per day may be efficacious; however the dose for prevention may be much less, even 80 mg/day, as suggested in the Ohio State University study If effective for prevention, treatment of MCI, treatment of Alzheimer's, the dose required may depend on stage. A published study from DiSilvestro et al. at Ohio State University, showed daily intake of 80 curcumin from Longvida reduced plasma levels of beta-amyloid as well as cholesterol and markers of inflammation plasma in subjects 40-60 years old.

Extensive toxicology conducted by the National Toxicology Program demonstrated that turmeric oleoresin (80% curcumin) is safe. As described in Title 21, Section 182.20 turmeric oleoresin is listed as one of the oils or oleoresins in plants as generally recognized as safe (GRAS) FDA's GRAS list. The European Food Safety Commission (EU), which has stricter requirements than the FDA for food safety, has also designated curcumin as safe.

However formulations that increase the free form also need to be tested for safety. Longvida Toxicity studies on Longvida find similar safety as compared to unformulated curcumin.

We are conducting a clinical trial to determine if Longvida is effective in Mild Cognitive Impairment on Brain Glucose Metabolism and Inflammatory Biomarkers. We have chosen s dose based on extrapolation from animal studies based on doses needed for neuroprotection and neuro anti-inflammatory properties testing whether 8 capsules daily may be sufficient. As with any drug, it is recommended to titer up to a dose slowly (1-2 capsules daily) then 2-4 capsules 2nd week and so on. Dose may depend on individual variabliity in absorption and formulation. Blood levels of free and metabolized curcumin are not typically measured, but are important to understand efficacious dose. Red blood cell or white blood cell (Buffy Coat) levels of free curcumin parallel brain levels, but not necessarily plasma levels, as plasma levels can be non-detectable when brain levels are high (Begum et al). It has a very short half life in plasma but a very long half life in brain because it is lipophilic (fat-loving) corresponding to its much higher concentrations in the fatty brain tissue than in blood.

When in relation to a meal should I take curcumin to limit its metabolism?

Fasting improves free curcumin absorption (eg. minimum of 3 hours after a meal). You make take it with a small drink (4-6 ounces; eg. cherry juice with a higher pH making it more soluble. Wait an hour before eating a meal. HOWEVER, ancectodal evidence suggests that some people may have sleep disturbances if taken before bedtime.

How will I know if curcumin is working?

Since there is no trial demonstrating effectiveness of curcumin in preventing Alzheimer's, we don't know how to answer this question until the trials have been conducted and completed. Anecdotal evidence suggests that slowly titering up and conducting self-administered memory tests can be helfpul in determining if it is helpful and at what dose. Some people use solitaire to monitor improvements. There maybe also be online tests to document memory changes. Since it takes 10 days to build up levels of curcumin in tissues, it may be important to titer up or down at 10 day intervals.

An immediate effect on memory has been describe anectdotally, but it would not necessarily be expected. In mouse studies spatial memory was measured after three months treatment. The most obvious initial effect would be a reduction in symptoms of joint pain or other inflammatory conditions. In one trial described here, only unformulated curcumin was used and free curcumin was relatively undetectable. Importantly, in extended results from the naproxen trial for Alzheimer's prevention, naproxen showed prevention of conversion to Alzheimer's; however, during the first year subjects’ memory worsened. It has not yet been determined whether lowering the dose until symptoms subside might avoid these deteriorations. Considering that we know that in animals curcumin clears out toxic amyloid and tau aggregates, it could conceivably transiently worsen memory. Although transient worsening of memory has not been observed in animals, it has been anecdotally been reported by some patients.

If I am considering taking curcumin with other nutraceuticals, what cocktail can I take?

Animal studies suggest that curcumin and fish oil synergize. It is very difficult to identify the nutraceuticals that synergize and those that counteract each other. Therefore, when exploring nutraceuticals it is important to add one at a time, for example at a minimum of 10-day intervals and monitor its effects.

Should I take DHA and curcumin together if I know I have the ApoE4 allele, making me at risk for Alzheimers? What form of DHA and how much?

Again clinical studies are necessary. Data suggest that subjects with E4 do not respond to DHA, which may be due to oxidation. It is possible that Curcumin or other antioxidants may enable ApoE4 to respond to DHA. A combination of pure DHA with fish oil would achieve a higher DHA to EPA ratio to avoid EPA competing for DHA incorporation into neuron membranes. The rationale for combining fish oil and DHA is that fish oil contains EPA, which may reduce risk for cardiovascular disease.

600-900 mg of DHA is recommended. Higher doses were used in the trial but there is saturation at 900 mg/day. One gram of fish oil has about 200 mg of DHA, so one could take 3-5 capules of fish oil. Or 2 capsules of Fish oil and 1 capsule of pure "algae" DHA. Fish oil impacts platelets, so watch for bruising and if on plavix, warfarin or related blood thinners, make sure to check clotting and adjust blood thinner appropriately.

More information about curcumin

  • Of the many polyphenolics, curcumin is special for the following reasons:

  • FAQS

    • One of many plant polyphenolics, curcumin is the Asian version of aspirin.  Our wonder drug aspirin was originally purified from willow bark extracts that were used in European and American Indian traditional medicines to control inflammation. Eventually aspirin was synthesized by German chemists and developed by Bayer as one of the most successful drugs in the Western medicine cabinet. Today aspirin is used not only in pain remedies and other analgesic applications, but to control minor fever and inflammation and, at low doses, to prevent heart attack and stroke.  Curcumin has been used in traditional Indian (Ayruvedic) and Chinese medicine for thousands of years largely because of its proven efficacy in treating conditions with inflammation. They also used it in foods as an effective food preservative, just as we use synthetic additives like BHA. These ancient civilizations have vast trial and error experience with many different herbal remedies and food preparations and they selected curcumin as a food additive and major tool for medicinal use based on efficacy- not superstition.
    • Curcumin is recognized by the National Cancer Institute (NCI) and academic investigators around the world as a potent anti-carcinogen. Because of low toxicity and great efficacy in multiple in vitro and in vivo cancer models, curcumin went through extensive toxicology testing and has successively made it through the first stages (Phase I) of clinical testing abroad; it is currently in clinical trials at several sites in the U.S. This work by many labs has provided the basis to quickly and safely explore curcumin’s potential for Alzheimer’s and other neurological diseases.
    • Curcumin has shown efficacy in many other pre-clinical culture and animal models for diseases related to aging. Treatments with related “curcuminoids” have even been able to increase the lifespan of mice.
    • Curcumin and Alzheimer ’s disease.  Our group has tested curcumin in several models and found that it not only reduces oxidative damage and inflammation (as expected), but also reduces amyloid accumulation and synaptic marker loss while promoting both amyloid phagocytosis and clearance. In in vitro studies, we found curcumin worked to prevent synaptic marker and cognitive deficits caused by amyloid peptide infusion and abeta oligomer toxicity. Our work on curcumin and AD is discussed in detail in our publications
  1. Curcumin suppresses soluble tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits in aged human tau transgenic mice. Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M, Teng E, Hu S, Chen PP, Maiti P, Teter B, Cole GM, Frautschy SA. J Biol Chem. 2013 Feb 8;288(6):4056-65.
  2. Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG, Porter V, Vanek Z, Marshall GA, Hellemann G, Sugar C, Masterman DL, Montine TJ, Cummings JL, Cole GM. Alzheimers Res Ther. 2012 Oct 29;4(5):43.
  3. Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease. Hickey MA, Zhu C, Medvedeva V, Lerner RP, Patassini S, Franich NR, Maiti P, Frautschy SA, Zeitlin S, Levine MS, Chesselet MF. Mol Neurodegener. 2012 Apr 4;7:12. doi: 10.1186/1750-1326-7-12.
  4. Why pleiotropic interventions are needed for Alzheimer's disease. Frautschy SA, Cole GM. Mol Neurobiol. 2010 Jun;41(2-3):392-409. doi: 10.1007/s12035-010-8137-1.
  5. . Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, Hudspeth B, Chen C, Zhao Y, Vinters HV, Frautschy SA, Cole GM. J Neurosci. 2009
  6. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease. Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, Cole GM, Frautschy SA. J Pharmacol Exp Ther. 2008 Jul;326(1):196-208. doi: 10.1124/jpet.108.137455.
  7. Heath DD, Pruitt MA, Brenner DE, Begum AN, Frautschy SA, Rock CL. Tetrahydrocurcumin in plasma and urine: Quantitation by high performance liquid chromatography.J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Jul 29; [Epub ahead of print]
    PMID: 16061427 [PubMed - as supplied by publisher]

  8. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL. A potential role of the curry spice curcumin in Alzheimer's disease.Curr Alzheimer Res. 2005 Apr;2(2):131-6.PMID: 15974909 [PubMed - in process]
  9. Cole GM, Morihara T, Lim GP, Yang F, Begum A, Frautschy SA. NSAID and Antioxidant Prevention of Alzheimer's Disease: Lessons from In Vitro and Animal Models.Ann N Y Acad Sci. 2004 Dec;1035:68-84.PMID: 15681801 [PubMed - in process]
  10. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo.
    J Biol Chem. 2005 Feb 18;280(7):5892-901. Epub 2004 Dec 7.PMID: 15590663 [PubMed - indexed for MEDLINE]
  11. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM. Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging. 2001 Nov-Dec;22(6):993-1005. PMID: 11755008 [PubMed - indexed for MEDLINE]
  12. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. Related Articles The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse.J Neurosci. 2001 Nov 1;21(21):8370-7.PMID: 11606625 [PubMed - indexed for MEDLINE
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