eved that he ate healthy meals and was healthy in other respects, even though his specific health problems worsened.

4.5. Curcumin Effects on First Exposure

The total beneficial effects of curcumin may be due to a variety of mechanisms acting at different levels, including direct regulation of the levels of neurotransmitters in the brain [8]. Thus, even in individuals who have never consistently eaten curry-containing dishes, beginning such a diet may result in beneficial epigenetic or other changes. This idea is supported by studies showing beneficial effects of curcumin in animals that had never been exposed to it [7-9]. Thus, it is possible that the improvement of the three symptoms described for the male subject in this report was due to three separate mechanisms mediated by curcumin.

4.6. Curcumin Effects on Fasting Blood Glucose

The man in this report has a history of mildly elevated fasting blood glucose (but no diabetes). Impaired glucose tolerance is known to cause small-fiber neuropathy that is potentially reversible [14]. As shown in Table 4, however, the history of elevated fasting glucose predated the onset of problems described for this male subject, there was no specific trend in blood glucose level except that the levels were slightly high throughout, and the results of HbA1c and a glucose tolerance tests were normal. Thus, the improvement in neuropathy was not likely due to major shifts in glucose. After almost 4 months of eating curry (twice daily, involving different vegetables) and regularly exercising (6 days a week, during the latter 2 months), the subject’s blood glucose level ultimately was lowered from 115 mg/dL (12/09/2004) to 93 mg/dL (07/07/2012) (Table 4). The subject never previously ate curry with such regularity as during the most recent 3 months and 3 weeks. Because dietary curcumin has been shown to significantly improve blood glucose levels in mouse models [15], and because of the well-known impact of exercise on blood glucose, the beneficial drop in blood glucose may be due to a combined or synergistic effect of eating curry and exercising. Prospective controlled human studies should help distinguish the contributions of curcumin and exercise to fasting blood glucose level.

5. Conclusion and Future Directions

The subject’s plasma curcumin levels are consistent with the conclusion that relief from his ailments was due to eating curry. Curcumin has many physiological and pharmacological effects. It is unclear, however, how this information about curcumin, especially in culinary amounts, translates to an individual’s plasma curcumin level and what the health status is of people who grew up eating curry but who stopped eating it for a prolonged period. This section reviews the literature on the pharmacokinetics of curcumin, again with the hypothesis that curcumin might be the key medicinally relevant component of curry. Further, this section presents possible reasons why curcumin levels are detectable in this first case and provides future directions to establish the clinical relevance of consuming curry.

5.1. Lack of Clinical Studies Comparing Curcumin Effects in Pure Form vs Curry Form

The present case may represent an unintended “experiment of nurture”, involving a relatively lengthy departure from a “normal” diet¾the one to which one is accustomed¾that resulted in pathophysiological consequences. Resuming such a diet may provide important insights, both theoretical and practical. Replicating the symptoms by repeating the curry deprivation would provide further support for the symptoms being due to the absence of curry, but the subject does not wish to re-experience the frightening visuospatial memory disturbances. Although the curry diet appears safe and effective, the limitations of this report are that it is based on one individual, and it was not blinded. The existing scientific literature focuses on the direct testing of curcumin itself, the active component of turmeric, rather than turmeric as a component of a meal. The chemical structure of curcumin (diferuloylmethane) is similar to that of the Congo Red pigment that stains amyloid (for review [4]). Based on human studies, curcumin’s bioavailability is reduced by hepatic and intestinal glucuronidation (for review [4]). Because it is poorly absorbed, co-administration of piperine (an alkaloid present in black pepper), which inhibits glucuronidation, may be needed to enhance its absorption [16]. Curcumin in doses > 2000 mg was needed to achieve measurable levels in human blood (for review [4]). In several human studies, curcumin up to 1200 mg/day was well tolerated (for review [4]). Although the literature on curcumin is extensive, basic or clinical studies comparing the bioavailability and effects of curcumin in pure form vs. curry form have not been published.

5.2. First Report of Curcumin Levels in a Curry Eater

Considering the beneficial effects reported in the present case report and epidemiologic data from India, it is reasonable to conclude that the curry formulation described here likely provides a therapeutically adequate amount of curcumin, although no published studies have documented curcumin levels in the blood and/or other tissues of curry eaters. However, unpublished results of V. Gota et al. involving three healthy curry eaters and a large number of participants with various illnesses in their clinical trials prior to dosing with curcumin (ACTREC, Tata Memorial Centre, Navi Mumbai, India, cited here with permission) showed undetectable plasma curcumin levels. This observation is likely because the levels were below the detection limit, in contrast to the plasma curcumin levels of the individual in the current study of 2.89 ng/mL (postprandial) and 4.56 ng/mL (fasting) (Table 5). All the participants in the above-mentioned study were regular curry eaters; however, it appears that they may not necessarily have cooked their curry dishes the same way as described in this report, and/or those participants may not have eaten curry with the same regularity as the man in this report who consumed curry over 3.5 months. The observation that the subject’s fasting level of curcumin was higher than the postprandial level is interesting and may reflect biological variation or the different curry sources consumed preceding each sample collection (green bell pepper vs valor beans). Another possibility is that the peak level in the postprandial sample had not been attained, as curcumin uptake may differ from that of glucose. These data are unlikely to be the result of intra-assay variation because a repeat analysis of a second set of sample aliquots also showed the fasting level to be higher than the postprandial level (Table 5).

5.3. Reasons for the Detectable Levels of Curcumin in a Curry Eater

The levels of curcumin detected in the subject’s blood are consistent with the literature. Curcumin has poor oral bioavailability, and no detectable plasma levels of curcumin have been observed in several previous clinical trials even after administering gram quantities of unformulated 95% curcuminoid extract [17,18]. In some studies (for example, “Curcumin and Gingerol protocol for MDS-UMASS Medical School”), even mega doses of curcumin (4 - 8 g/day, and sometimes 12 g/day) are well tolerated, a claim that is unlikely to be useful because there is no evidence that curcumin is absorbed into the bloodstream. Blood plasma seems to contain the lowest amount of curcumin compared to other tissues following oral administration in rats [19]. The reasons for the detectable levels of curcumin in the blood of the individual in the current report are probably three-fold: 1) The curry formulation favors improved absorption. Curcumin is a lipid-soluble compound, and two of the ingredients in the curry dish described are lipids (olive oil and coconut powder), which likely aided its absorption; 2) The subject not only ate curry but also mixed it with yogurt (as a habit) and some grains. Such a culinary practice apparently has a favorable clinical effect, as yogurt was a good delivery system for curcumin in a rat model [20]. Chemical or other types of interactions, if any, between curcumin and yogurt components, such as organic acids, remain to be investigated; 3) As a consequence of regular curry consumption for 3.5 months, the curcumin in the subject’s system was probably equilibrated between the blood and other organs/tissues, resulting in a detectable amount in the circulation. The amount of curcumin consumed by the subject with each meal was relatively small because he added ~1/2 tsp turmeric (~1.25 g) to the curry dish (see Supplementary Appendix), divided the curry dish, and ate it with four meals, i.e., ~312 mg turmeric per meal. Considering that curcumin represents only 2% - 5% of turmeric [21], the intake of curcumin per meal was estimated at 6 - 15 mg, which is small compared to the gram quantities of curcumin administered in clinical trials. Thus, it is indeed remarkable that curcumin was detectable in the subject’s blood. The levels more likely reflect the body’s store of curcumin that accumulated over 3.5 months rather than from recent meals; the relevant pharmacokinetic mechanisms remain to be investigated.

5.4. Summary of Observations of the Present Case

The important observations from this case study are: 1) Consumption of large quantities of curcumin may not be necessary to achieve therapeutic benefits because such benefits were attained even with relatively low-level consumption by the subject in this case study; 2) The plasma curcumin levels of the subject were high compared with levels of regular curry eaters in India, but they were not as high as the levels obtained using formulated curcumins, such as Solid Lipid Curcumin Particle (22.43 ng/mL) [17] or Theracurmin (275 ± 67 ng/mL) [18]. However, potential deleterious effects of maintaining such high levels of plasma curcumin over the long-term are not known; 3) Moreover, higher levels of curcumin may not necessarily be more biologically effective because curcumin shows biphasic effects on cultured neural progenitor cells; low concentrations stimulate cell proliferation, whereas high concentrations are cytotoxic [7]. Of course, eating curry, as opposed to taking curcumin tablets, has additional health benefits because one is simultaneously eating a variety of vegetables and greens. The curry formulation presented in this report, although complex, has at least one measurable end analyte, namely curcumin. Because the curry recipe described here contains defined ingredients and the curry dish thus prepared is easily tolerated in the diet, it is amenable to a clinical trial. A randomized controlled clinical study could best determine the possible health benefits of eating curry. To facilitate large-scale clinical trials, the current lowthroughput, labor-intensive high-performance liquid chromatography methodology for measuring plasma curcumin levels should be replaced with a relatively inexpensive and practical assay. Eating curry over a long period may result in somewhat of a biological dependency, as evidenced by some of the long-term withdrawal effects described in this case report. Perhaps Indian physicians in the US and elsewhere will come forward to report any Indian patients who may have experienced a similar phenomenon.

In summary, although this is a case report, it has a high probability of being generalizable to other curry eaters. The data on the subject’s curcumin levels reinforce the objectivity of the report. This is the first report of curcumin levels in a curry eater. This report should provide a framework for future clinical and laboratory investigations and bring rapid advances to the field, targeting the individual person as the focus of investigation, and thus filling the void that exists between population-based epidemiologic data and cellular-based fundamental biological investigations of curcumin.

6. Acknowledgements

I thank Kousalya Reddy Chada and Narayanadas Vakamudi for helpful discussions. Dr. Marshall A. Lichtman (University of Rochester, NY) critically read the manuscript and made valuable comments and suggestions. Dr. Greg M. Cole (University of California, Los Angeles) carefully read the manuscript and drew my attention to published studies on the effects of curry consumption as related to cognitive function in the elderly and cancer incidence in emigrant Indians. I am grateful to Dr. Vikram Gota (ACTREC, Tata Memorial Centre, Navi Mumbai, India) for help with measuring the plasma curcumin levels in this case. I also thank Dr. Gota for sharing the unpublished results involving the curcumin levels of curry eaters. Finally, I thank Dr. C. C. Di Stasio, Dr. A. Chopra, and Dr. N. R. Doshi, physicians at Kaiser Permanente, for reviewing this report for accuracy of the clinical data and for their comments.

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Supplementary Appendix

Seshi’s Basic Curry Recipe

Three variations can be prepared: 1) plain; 2) tomatobased; and 3) tamarind-based. In the interest of time efficiency, make two curry dishes of a given variation side by side.

1) Wash the vegetable of choice (~2.0 lb) as appropriate (generally by soaking for 10 min in 1.25% distilled white vinegar, followed by rinsing in water);

2) Peel the vegetable, if required;

3) Cut the vegetable into small, bite-sized cubes;

4) Transfer the pieces to a flat-bottom pot (such as a vegetable steamer or a pressure cooker base), add just enough water to cover the pieces, and 1 tbsp iodized salt. Bring water to boil, and let vegetables boil for 2 min or until wilted;

5) Transfer the vegetable pieces to a salad spinner with running cold water, rinse 2 - 3 times, spin dry, and set them aside. Steps 4 and 5 a) minimize the rawness of vegetables, b) cleanse off pesticides, and c) ensure adequate cooking of vegetables, and consequently make vegetables easily tolerated by the gastrointestinal tract;

6) Repeat steps 1 - 5 for the second vegetable;

7) For tomato-based curry: Wash and cut four medium-sized tomatoes, and set the cut pieces aside;

8) For tamarind-based curry: Take tamarind of the size of two lemons, add 2 cups of water, microwave for 2 min, let cool, squeeze and strain the juice out, and set aside (Never use a pre-made commercial tamarind paste because it will adversely affect the taste);

9) Cut one large yellow onion using an onion chopper, and set the chopped onion aside;

10) Wash curry leaves (two twigs; Murraya koenigii), wipe the leaves dry, and set them aside;

11) Heat frying pan on low-to-medium heat (150˚F if on an induction hotplate). Then, sequentially add the following ingredients:

    a) 4 - 6 tbsp cooking olive oil;

    b) Curry leaves (a taste booster), once aroma begins, add the next item;

    c) Chopped onion;

    d) 1 tbsp iodized salt;

    e) Turmeric (1/2 tsp) (provides color and enhances taste).

Continue mixing the contents until the onion pieces turn translucent (glistening).

For plain or tamarind-based curry: transfer 1/2 of the contents to a second frying pan.

For tomato-based curry: add tomato pieces to the above, and continue cooking for ~10 min until the mixture thickens. Then, transfer 1/2 of the contents to a second frying pan.

12) Add the pre-boiled vegetable and 1/4 to 1/2 cup water (depending on how soft you want to cook it, as it needs to be cooked until all the water is fully absorbed) to the above mixture in each pan. Cook until the mixture thickens and water is gone. Check and add salt to taste.

For tamarind-based curry: add 1 cup tamarind juice, in addition to or instead of water, to the mixture in each frying pan, and cook until the gravy achieves desired consistency. Add salt and sugar (to taste).

13) Finally, add 1/2 tbsp chili powder and 1 tbsp dry coconut powder (another taste booster, in addition to curry leaves) to each mixture;

14) Continue cooking for an additional 2 min. Turn off heat.

Notes

1) For plain curry, the procedure may be carried through 12 - 14 steps; or after step 11, add chili powder and coconut powder to the contents, mix, and cook for 2 min, and then add the pre-boiled vegetables (no water), mix, and transfer the contents to a baking pan, cover with aluminum foil, and bake for 20 min at 400˚F. As this baking part is performed unattended, it is a time saver;

2) Approximately 2.0 lb vegetable will yield a curry dish of approximately four servings. A serving is defined as the amount of curry eaten with a meal, such as lunch or dinner. The vegetables regularly cooked using the described method are those that are typically cooked in an Indian household: okra, green beans, gavar beans or cluster beans (Cyamopsis tetragonoloba), bitter melon, tindora (Coccinia grandis, the ivy gourd), taro root, toor dhal (Pisum sativum; pressure-cooked first), bottle gourd (Lagenaria siceraria), ridge gourd (Lufa acutangula), mixed greens (a mix of fresh spinach, mustard greens, turnip greens, and collard greens, as commercially sold), green bell pepper, broccoli, and cauliflower; onion by itself as a vegetable. Of course, other vegetables may also be considered, as per taste;

3) In the initial search to find a solution to the subject’s neuropathic pain, he first learned to cook a variety of whole grains like one would cook rice. He has been eating them for several years. He has thus been eating “healthy” otherwise and is healthy in other respects, but that did not help with the particular problems described here. He continues to eat different grains, but mixed with different curries;

4) Although the vegetable curry as described has been the main source of the subject’s curcumin, he also receives it in other minor ways, as he sometimes eats an egg omelet (prepared including salt and black pepper, plus turmeric, the latter mixed in olive oil first), and salmon and chicken dishes (prepared including turmeric, some ginger and lemon juice). Sometimes, before going to bed, or if he wakes up at night, he may drink a cup of warm whole milk with a pinch of turmeric and a spoonful of brown sugar or honey or a malted chocolate drink, Bourn-Vita, added to it. Alternatively, he may drink a cup of warm whole milk with a pinch each of salt and black pepper plus turmeric added to it. These additions fully account for his dietary sources of curcumin.

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