Hydration: How much do you need?

waterWe have been counseled to drink eight, 8-ounce glasses of water a day (8 x 8) for such a long time that the advice has become unwritten law…and slavishly followed at that. This chant started so long ago that most people have no idea of its origin. At the same time, we are cautioned not to count alcohol and coffee as hydration elements. The science behind the recommendation is so scant that little support can be given to the exhortation, yet the possession of a water bottle is ubiquitous. It is possible that this idea is the result of misinterpretation or misreading of a notion proposed by the Food and Nutrition Board of the National Research Council that recommended one milliliter of water for every calorie consumed. The neglected fact is that there is water in our food. That would surely separate liquid intake from total dietary intake.

Dr. Heinz Valtin, a medical professor at Dartmouth, examined this mantra earlier in this century, and learned, “No scientific studies were found in support of 8 x 8.”  After reviewing surveys of food and fluid intake on thousands of adults of both genders, Dr. Valtin stated that, “…such large amounts (of water) are not needed because the surveyed persons were presumably healthy and certainly not overtly ill.”  He added that most other kinds of beverages, including soft drinks and coffee, contribute to one’s daily need for hydration, continuing that a considerable body of evidence supports the premise that the human body is fully capable of maintaining proper water balance.  But all this must be tempered with the qualifier, “in healthy persons.”  He leaves us with, “…large intakes of fluid, equal to and greater than 8 x 8, are advisable for the treatment or prevention of some diseases and certainly are called for under special circumstances, such as vigorous work and exercise, especially in hot climates.”  In the spirit of open-mindedness, Dr. Valtin asks that readers submit their own findings to him.

Including the 20% supplied by foods, the Institute of Medicine recommends a fluid intake of about 91 ounces a day for women and 125 ounces for men.  Do you know how much water is in your food?  Few of us do. The puzzling thing about this recommendation is the lack of sufficient data available on water metabolism in adults, especially those who are sedentary and living in a temperate environment.  Most of us take in more than that suggested level, when we account for comestibles, although the geriatric populace is apt to take in less of both food and liquid water, partly because of insensitivity to a thirst stimulus and partly because of a waning ability to taste foods and beverages as well as they did in their early years.  It appears that older men drink less than their younger counterparts, but excrete more urine.  Differences in women have shown to be insignificant, but contribute to the notion that, “water turnover is highly variable among individuals…”  (Raman et al. 2004)

Admittedly, older adults are at greater risk for dehydration, but water balance in this population had not been faithfully studied until Purdue University picked up the reins in 2005, and compared/contrasted water intake/output and total balance of fluids in an older population (63-81 y.o.) and a younger one (23-46 y.o.), finding that, in fat-free mass, there is little difference.  The study noted, though, that fat-free mass was lower in the elderly and that fat-free hydration was significantly higher.  Considering that the elderly have less muscle to begin with, this is simple to follow.  (Bossingham. 2005)

Many people complain that, if they increase water intake, they will spend more time in the lavatory.  While this is the case with many of us, there is a limiting factor—time.  The period of time over which a specific amount of water is consumed makes a difference in when the urge to evacuate that water will arise.  The faster you drink that glass of water, the sooner you will need to excrete it.  The longer the glass lasts, the more time there will be prior to evacuation.  “A water diuresis occurs when a large volume of water is ingested rapidly.”  (Shafiee. 2005)   Also note that water mixed with a poorly absorbed sugar (not glucose) will retard absorption and delay excretion.

The kidneys can process almost four gallons of water a day.  Too much water will make you sick because sodium stores will become depleted and electrolyte activity will be sorely jeopardized.  Drinking over a period of time can thwart this threat.  You need not measure urine output to figure out how much fluid to replace.  That is something you can eyeball.  Thirst should not be the barometer by which fluid need is determined.  While there is no absolute proof that we all need 8 x 8, have a glass of water even when you are not thirsty, working in the heat, or running a marathon.  To prevent electrolyte displacement, we might consider electrolyte replacement in at least a couple of our glasses.


Am J Physiol Regul Integr Comp Physiol. November 2002; vol. 283 no. 5: R993-R1004
“Drink at least eight glasses of water a day.” Really? Is there scientific evidence for “8 × 8”? Heinz Valtin and (With the Technical Assistance of Sheila A. Gorman)

Am J Physiol Renal Physiol. 2004 Feb; 286(2):F394-401. Epub 2003 Nov 4.
Water turnover in 458 American adults 40-79 yr of age. Raman A, Schoeller DA, Subar AF, Troiano RP, Schatzkin A, Harris T, Bauer D, Bingham SA, Everhart JE, Newman AB, Tylavsky FA.
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

Am J Clin Nutr. 2005 Jun; 81(6):1342-50.
Water balance, hydration status, and fat-free mass hydration in younger and older adults. Bossingham MJ, Carnell NS, Campbell WW.
Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907, USA.

Kidney Int. 2005 Feb;67(2):613-21.
Defining conditions that lead to the retention of water: the importance of the arterial sodium concentration. Shafiee MA, Charest AF, Cheema-Dhadli S, Glick DN, Napolova O, Roozbeh J, Semenova E, Sharman A, Halperin ML.

Renal Division, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada.

Am J Physiol Regul Integr Comp Physiol. 2000 Sep;279(3):R966-73.
Effects of time of day, gender, and menstrual cycle phase on the human response to a water load. Claybaugh JR, Sato AK, Crosswhite LK, Hassell LH.

Department of Clinical Investigation, Tripler Army Medical Center, Tripler Army Medical Center, Hawaii 96859 – 5000. [email protected]

Eur J Clin Nutr. 2010 Feb;64(2):115-23. Epub 2009 Sep 2.
Water as an essential nutrient: the physiological basis of hydration. Jéquier E, Constant F.
Department of Physiology, University of Lausanne, Pully, Switzerland. [email protected]

J Am Soc Nephrol 19: 1041-1043, 2008
Just Add Water
Dan Negoianu and Stanley Goldfarb

Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Lack Of Sleep Alters Hormones, Affects Weight

male-sleepySleep disorders are coming under closer scrutiny in a society plagued by their ubiquity, prompted by extraneous and self-induced pressures and obligations.  Discovery of the genetic basis for circadian rhythms has expanded our knowledge of the temporal role of behavior and physiology.  The relationship between sleep deprivation and hormone imbalance is publicized, but disregarded.  That part of the hypothalamus in charge of daily metabolic rhythm is called the suprachiasmatic nucleus, and it controls physical activity and hormone levels, as well as sleep, body temperature, immunity, and digestion.

Sleep deprivation, or even fragmentation, interrupts the machinery that controls energy expenditure and food intake.  A single night of sleep deprivation has been found to increase the risk of obesity by disturbing secretion and function of thyrotropin, cortisol and ghrelin (Benedict. 2011).  Thyrotropin is better known as TSH, the pituitary secretion that regulates the endocrine function of the thyroid gland.   Cortisol is excreted by the adrenal glands to address stress, affecting the metabolism of glucose, protein and fats. Ghrelin regulates appetite by telling you to eat, while its partner, leptin, tells you to stop.  Aberrations of these substances, aggravated by lack of sleep, reduce expenditure of energy during the waking hours.  Because fewer calories are burned, weight gain is almost certain.  Although the mechanisms behind it are not completely understood, “epidemiological evidence indicates that chronic sleep curtailment increases risk of developing obesity.” (Ibid.).

When we run low on energy from lack of sleep, many of us grab a coffee or three and a handful of junk to get a quick fix of comfort food.  That doesn’t last very long, though, does it?  Sleep affects one’s ability to maintain or to lose weight by regulating hormones and metabolism, which includes the way we handle food as part of the range of processes that occur within a living organism.  This entails anabolism (buildup) and catabolism (break down).  Deprivation of sleep is also tied to cardiovascular health and inflammation that is below the radar, called subclinical (Sharma. 2010).

We need about seven and a half hours of sleep each night.  An extra half hour, by the way, won’t help you to lose the last ten pounds.  But moving from five hours to eight might just be able to accomplish that.  It’s all in the hormones.  If you’re sleep-deprived, you have higher levels of ghrelin, telling you to eat.  That means that leptin is in short supply, and you’ll eat more than you need, ending up with more calories in and fewer calories out.  Oops, imbalance.

Apnea, bruxism (teeth grinding), narcolepsy, and insomnia are only a few of the sleep disorders that plague us.  Overcoming these insults can prevent the health conditions that stem from their upswing in modern society.  Besides obesity, impaired glucose tolerance and insulin resistance are real threats.  Losing some sleep for only a single night can upset the apple cart of insulin sensitivity (Donga. 2010).  That may be of significant relevance to a person harboring Type 2 diabetes, and most assuredly will be with Type 1.  What’s interesting is that voluntary sleep deprivation is a characteristic of modern life, where people put more stock into their jobs than into themselves and their families (Bosy-Westphal. 2008).  Here, weight gain from increased energy intake is earned, even without conscious thought.  Once the inborn clock gets out of whack, don’t be surprised by physiological dysregulation of one kind or another (Huang. 2011).

Sleeping as little as possible is not admirable behavior.  High-schoolers and students cramming for college exams are not doing themselves any favors.  Neither is the mom or dad who works into the wee hours, a common activity in industrialized nations.  Since the 90’s, researchers have paralleled sleep deprivation with the rise of obesity, especially in kids (Leproult. 2010) (Knutson. 2008).  Since our hormones vary from day to night, it matters that we keep circadian rhythm aligned with the design of their function.  Shut off the TV and get rid of the computer games at bedtime.  Put the cell phone away while you’re at it.


Benedict C, Hallschmid M, Lassen A, Mahnke C, Schultes B, Schiöth HB, Born J, Lange T.
Acute sleep deprivation reduces energy expenditure in healthy men.
Am J Clin Nutr. 2011 Jun;93(6):1229-36.

Sunil Sharma and Mani Kavuru
Sleep and Metabolism: An Overview
International Journal of Endocrinology. Vol. 2010 (2010), Article ID 270832, 12 pages

Donga E, van Dijk M, van Dijk JG, Biermasz NR, Lammers GJ, van Kralingen KW, Corssmit EP, Romijn JA.
A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects.
J Clin Endocrinol Metab. 2010 Jun;95(6):2963-8.

Bosy-Westphal A, Hinrichs S, Jauch-Chara K, Hitze B, Later W, Wilms B, Settler U, Peters A, Kiosz D, Muller MJ.
Influence of partial sleep deprivation on energy balance and insulin sensitivity in healthy women.
Obes Facts. 2008;1(5):266-73.

Wenyu Huang, Kathryn Moynihan Ramsey, Biliana Marcheva1,and Joseph Bass
Circadian rhythms, sleep, and metabolism
J Clin Invest. 2011;121(6):2133–2141.

Leproult R, Van Cauter E.
Role of sleep and sleep loss in hormonal release and metabolism.
Endocr Dev. 2010;17:11-21.

Knutson KL, Van Cauter E.
Associations between sleep loss and increased risk of obesity and diabetes.
Ann N Y Acad Sci. 2008;1129:287-304.

Spiegel K, Tasali E, Leproult R, Van Cauter E.
Effects of poor and short sleep on glucose metabolism and obesity risk.
Nat Rev Endocrinol. 2009 May;5(5):253-61.

Morris CJ, Aeschbach D, Scheer FA.
Circadian system, sleep and endocrinology.
Mol Cell Endocrinol. 2011 Sep 10. [Epub ahead of print]

Beccuti G, Pannain S.
Sleep and obesity.
Curr Opin Clin Nutr Metab Care. 2011 Jul;14(4):402-12.

Spiegel K, Leproult R, L’hermite-Balériaux M, Copinschi G, Penev PD, Van Cauter E
Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin.
J Clin Endocrinol Metab. 2004 Nov;89(11):5762-71.

Nedeltcheva AV, Kessler L, Imperial J, Penev PD.
Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance.
J Clin Endocrinol Metab. 2009 Sep;94(9):3242-50. Epub 2009 Jun 30.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Gallstones: An Ounce Of Prevention Is Worth…

basic-food-groupIf you have some gall, we hope it’s the kind that causes you to exasperate others, and not the kind that hurts in the center of your upper belly, under the ribs, and occasionally spreads to your right upper back or shoulder.  Gallstone disease is the most common and costly of all the digestive conditions in the United States, accounting for nearly a million hospitalizations a year.  It can interfere with breathing and become severe enough to wake you from sleep…if you can get there in the first place.  Sometimes a person will vomit and relieve the pain; at other times he’ll get feverish from an outright blockage of the bile duct that connects the liver and gall bladder to the small intestine.  With a blockage, urine turns dark, stools are clay-colored, and the whites of the eyes may yellow.  We hope it never gets this far.

While allopathic medicine preaches no sure way to prevent gallstones, it allows that there are means to reduce risk.  Staying close to your ideal weight is important.  A real concern with this is that, lately, everybody is jumping onto the “lose weight fast” bandwagon.  It seems that gallstones can form from such a regimen and even from gastric bypass surgery (Shiffman, 1991).   In obesity, bile tends to stand still and cholesterol saturation increases.  Stones can form within a month of severe caloric restriction, as much as twenty-five times more likely than in obese persons who lose weight gradually (Weinsier, 1993).  Once in a while a person gets lucky, and there are no symptoms, despite the fact that most middle-agers probably have small stones.

Whether it was intended to be a mnemonic or not, the association of the “Five F’s” with gallbladder disease has been around for a time.  Female, fair (hair and skin), forty-ish, fertile (gallbladder trouble is associated with high estrogen), and owning too much fat risk gallstones.  But alcohol intake, a high-fat diet (especially fried foods) and sedentary lifestyle are contributing factors.  In an acute gallbladder attack, people will generally go to the ER, where they will get antibiotics and medicine for the pain, which will probably go away.  If an obstruction is noted, surgery will be done.  In a chronic gallbladder condition, surgery, either traditional or laparoscopic, will remove the gallbladder.  In circumstances that can be pinpointed only by a physician, medications called chenodeoxycholic acids or ursodeoxycholic acids can be given to help dissolve the stones.  But this can take as long as two years and the stones often reappear after treatment is stopped.

It is advisable that, if you are prone to gallbladder problems, you eat a low-fat, low-sugar, high fiber diet.  Decreasing fat limits the amount of work the gallbladder has to do every day.  Increasing fiber helps the liver to eliminate toxins faster. Besides, anything that supports liver function also helps it to make more bile.  Alternative treatment of gallbladder disease relies on increased bile production, liquefaction of bile to help get rid of gallbladder sludge, and dissolution of stones so they can be reduced to a size that can pass naturally. Production of bile can be increased with foods that reduce toxic burden on the whole body, including beets, artichokes (Saénz Rodriguez, 2002), greens, and cruciferous vegetables (Tsai, 2006).  Acidulated water also stimulates liver function. Even a shot of unfiltered apple cider vinegar can help.

Since an ounce or prevention is worth more than a ton of cure, take a look at what coffee does for gallbladder disease.  Harvard scientists found that increased intake of caffeinated beverages reduces the risk of symptomatic gallbladder disease in men, while decaf demonstrated no such effect (Leitzmann, 1999).  In a ten-year study of male healthcare professionals, the incidence of gallbladder attacks was significantly lower in those consuming coffee regularly.   A novice coffee drinker might get the jitters and act like Barney Fife charging his cylinder, but the tradeoff is worth it.  Later study by the same researcher discovered a parallel benefit for women (Leitzmann, 2002).  Using ultra-sound to document gallbladder disease, the Third National Health and Nutrition Examination found that, among women, there was a decreased prevalence of previously diagnosed gallbladder disease with increased coffee drinking (Ruhl, 2000).

Primates and guinea pigs are unable to create vitamin C from diet, so supplementation is required.  The enzyme needed to convert glucose into ascorbic acid was lost eons ago.  Without vitamin C, even guinea pigs get gallstones, although we have never seen tiny guinea pig ambulances in our neighborhood.  From the same health and nutrition exam cited earlier, which ran from 1988 to 1994, researchers from the V.A. Center in San Francisco saw an inverse relationship between vitamin C intake and gallstones, strongly so among women, less so among men (Simon, 1998, 2000).  Vitamin C, by the way, affects the catabolism of cholesterol to bile acids.  Using guinea pigs as, well, guinea pigs, Swedish investigators learned that deficiency of vitamin C causes supersaturation of bile and the subsequent formation of cholesterol gallstones.  But they also found an interesting side story in humans.  Increasing ascorbic acid also increases phospholipid concentrations, leading to a strong inverse association with the conditions that lead to stone formation (Gstafsson, 1997).  German scientists came to the same conclusion about ascorbic acid when they found half the incidence of gallstones in a female population that supplemented with vitamin C regularly (Walcher, 2009) (Lammert, 2004).

So far, prevention has addressed measures that are readily available, off the shelf.  An important strategy to prevent stone formation if one is susceptible is to alter the conditions that promote it.  That can be done with phosphatidylcholine (PC), the chief phospholipid from which the cell membrane is made.  Enriching your diet with PC can directly affect cholesterol solubilization and reduce or eliminate the probability of gallstone formation (Kasbo, 2003) (Vakhrushev, 2005) (Lammert, 2004).

Anecdotal reports about healing protocols abound.  But some of them are surprisingly supportable.  When a person is hospitalized for gallbladder disease, his food is typically replaced with intravenous fluids.  In a while, the pain goes away, after which time you’re allowed to eat.  It’s believed that some foods invoke an allergic response that is at the root of gallbladder attacks.  In a casual test done in the late 1960’s, Dr. James Breneman, the chair of the Food Allergy Committee of the American College of Allergists, asked 69 people suffering from gallbladder pain to try an elimination diet to determine food allergies.  After the identified foods were taken from their diets, symptoms disappeared.  The offending foods were tagged.  Eggs, pork, onions, chicken and turkey, milk, coffee, and oranges were most bothersome, followed by corn, beans, nuts, spices, peanuts, fish and rye.  In addition to foods, twenty percent of the group had attacks caused by medications (Wright, 2004).

Pain and the fear of surgery will direct a person to the least invasive solution he can find, whether it’s clinically proven or not.  There is at least one such remedy for gallstone dissolution that seems to be popular outside the U.S.—a gallbladder cleanse purportedly designed by a Korean chemist named Dr. Lai Chiu Nan.  It entails drinking four glasses of apple juice (or eating four-five apples) daily for five days.  The juice is supposed to soften the stones.  Maintain a normal diet during this time.  On day six, no dinner is enjoyed.  At 6 PM, a teaspoon of Epsom salts in a glass of warm water is consumed, followed by a second such cocktail two hours later.  Magnesium sulfate opens the gallbladder ducts (Harvey, 1973).  At 10 PM, swallow a half cup of olive oil mixed with a half cup of fresh lemon juice, to lubricate the stones and to ease their passage.  Green stones are supposed to drop into the toilet the next day.  If they don’t, use the olive oil and lemon juice to make vinaigrette.  If they do, a gemologist might make you an offer.  Hey, sometimes folk medicine really works, as in the oatmeal baths for itchy skin or lemon juice and honey for a sore throat.

Bile synthesis has been improved and increased by taking essential fatty acids, most notably fish oil.  In a head-to-head contest with fibrates (drugs used to lower triglycerides and cholesterol), fish oil was found to up the ante on bile acids and to alter their distribution (Jonkers, 2006).  But this wasn’t the first time that fish oil stood in the limelight.  Gall bladder emptying increases with fish oil, as gall bladder motility improves and triglyceride levels drop (Jonkers, 2003).  And it sure works on monkeys (Scobey, 1991).  In prairie dogs, who must be kin to guinea pigs because they are prone to gallstones, menhaden oil (an occasional source of commercial fish oil) increased levels of EPA and DHA and reduced incidence of cholesterol crystals (Booker, 1990).

We normally think of solvents as able to dissolve things, but almost never relate them to the human body except in old Vincent Price movies.  Some scientists might disagree with this neglect because they have learned that gallstones can sometimes be dissolved by plant-sourced solvents, especially a terpene called limonene, common to citrus fruits and recognized as a safe flavoring agent in foods and beverages.  An unsaturated hydrocarbon from plants, limonene has been tried and proven to be a dissolver of cholesterol stones (Sun, 2007), while a welcome side effect is the relief of heartburn and GERD (Ibid.).  In a trial dating back to the 1970’s, a blend of limonene and polysorbate 80 (an emulsifier) was found safe and effective in the lab and the clinic (Igimi, 1976).  Occasionally following gallbladder surgery, stones are retained in the duct.  Injecting a limonene preparation directly to the biliary system was able to dissolve retained stones (Igmini, 1991).  Efficacy was enhanced when limonene was mixed with a medium-chain triglyceride in a Japanese study done toward the end of the last century (Shionogi, 1992).  Besides citrus, a readily available source of such solvent is peppermint oil.  Whether it works orally to dissolve gallstones is under investigation.  It’s doubtful that some of us can wait for the results to be printed.


Baranyai T, Terzin V, Vajda A, Wittmann T, Czakó L.
[Acute pancreatitis caused by hypertriglyceridemia].  [Article in Hungarian]
Orv Hetil. 2010 Nov 7;151(45):1869-74.

Booker ML, Scott TE, La Morte WW.
Effects of dietary fish oil on biliary phospholipids and prostaglandin synthesis in the cholesterol-fed prairie dog.
Lipids. 1990 Jan;25(1):27-32.

Doran J, Keighley MR, Bell GD.
Rowachol–a possible treatment for cholesterol gallstones.
Gut. 1979 Apr;20(4):312-7.

Gaby AR.
Nutritional approaches to prevention and treatment of gallstones.
Altern Med Rev. 2009 Sep;14(3):258-67.

Gilat T, Leikin-Frenkel A, Goldiner L, Laufer H, Halpern Z, Konikoff FM.
Arachidyl amido cholanoic acid (Aramchol) is a cholesterol solubilizer and prevents the formation of cholesterol gallstones in inbred mice.
Lipids. 2001 Oct;36(10):1135-40.

Gustafsson U, Wang FH, Axelson M, Kallner A, Sahlin S, Einarsson K.
The effect of vitamin C in high doses on plasma and biliary lipid composition in patients with cholesterol gallstones: prolongation of the nucleation time.
Eur J Clin Invest. 1997 May;27(5):387-91

Effects of oral magnesium sulphate on colonic motility in patients with the irritable bowel syndrome’
Gut, 1973, 14, 983-987

Igimi H, Hisatsugu T, Nishimura M.
The use of d-limonene preparation as a dissolving agent of gallstones
Am J Dig Dis. 1976 Nov;21(11):926-39.

Igimi H, Tamura R, Toraishi K, Yamamoto F, Kataoka A, Ikejiri Y, Hisatsugu T, Shimura H.
Medical dissolution of gallstones. Clinical experience of d-limonene as a simple, safe, and effective solvent.
Dig Dis Sci. 1991 Feb;36(2):200-8.

Igimi H, Watanabe D, Yamamoto F, Asakawa S, Toraishi K, Shimura H.
A useful cholesterol solvent for medical dissolution of gallstones.
Gastroenterol Jpn. 1992 Aug;27(4):536-45.

Jonkers IJ, Smelt AH, Ledeboer M, Hollum ME, Biemond I, Kuipers F, Stellaard F, Boverhof R, Meinders AE, Lamers CH, Masclee AA.
Gall bladder dysmotility: a risk factor for gall stone formation in hypertriglyceridaemia and reversal on triglyceride lowering therapy by bezafibrate and fish oil.
Gut. 2003 Jan;52(1):109-15.

Jonkers IJ, Smelt AH, Princen HM, Kuipers F, Romijn JA, Boverhof R, Masclee AA, Stellaard F.
Fish oil increases bile acid synthesis in male patients with hypertriglyceridemia.
J Nutr. 2006 Apr;136(4):987-91.

Kasbo J, Tuchweber B, Perwaiz S, Bouchard G, Lafont H, Domingo N, Chanussot F, Yousef IM
Phosphatidylcholine-enriched diet prevents gallstone formation in mice susceptible to cholelithiasis.
J Lipid Res. 2003 Dec;44(12):2297-303. Epub 2003 Jul 1.

Kraft K.
Artichoke leaf extract- recent findings reflecting effects on lipid metabolism, liver and gastrointestinal tracts.
Phytomedicine 1997;4:369-78.

Lammert F, Matern S.
Evidence-based prevention of cholecystolithiasis.
Dtsch Med Wochenschr. 2004 Jul 9;129(28-29):1548-50.

Leitzmann MF, Willett WC, Rimm EB, Stampfer MJ, Spiegelman D, Colditz GA, Giovannucci E.
A prospective study of coffee consumption and the risk of symptomatic gallstone disease in men.
JAMA. 1999 Jun 9;281(22):2106-12.

Leitzmann MF, Stampfer MJ, Willett WC, Spiegelman D, Colditz GA, Giovannucci EL.
Coffee intake is associated with lower risk of symptomatic gallstone disease in women.
Gastroenterology. 2002 Dec;123(6):1823-30.

Riber C, Hojgaard L, Madsen JL, Rehfeld JF, Olsen O.
Gallbladder emptying and cholecystokinin response to fish oil and trioleate ingestion.
Digestion. 1996;57(3):161-4.

Ruhl CE, Everhart JE.
Association of coffee consumption with gallbladder disease.
Am J Epidemiol. 2000 Dec 1;152(11):1034-8.

Saénz Rodriguez T, García Giménez D, de la Puerta Vázquez R.
Choleretic activity and biliary elimination of lipids and bile acids induced by an artichoke leaf extract in rats.
Phytomedicine. 2002 Dec;9(8):687-93.

Scobey MW, Johnson FL, Parks JS, Rudel LL.
Dietary fish oil effects on biliary lipid secretion and cholesterol gallstone formation in the African green monkey.
Hepatology. 1991 Oct;14(4 Pt 1):679-84.

Shiffman ML, Sugerman HJ, Kellum JM, Brewer WH, Moore EW.
Gallstone formation after rapid weight loss: a prospective study in patients undergoing gastric bypass surgery for treatment of morbid obesity.
Am J Gastroenterol. 1991 Aug;86(8):1000-5.

Simon JA, Hudes ES.
Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III).
Arch Intern Med. 2000 Apr 10;160(7):931-6.

Simon JA, Hudes ES.
Serum ascorbic acid and other correlates of gallbladder disease among US adults.
Am J Public Health. 1998 Aug;88(8):1208-12.

Sun J.
D-Limonene: safety and clinical applications.
Altern Med Rev. 2007 Sep;12(3):259-64.

Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL.
Fruit and vegetable consumption and risk of cholecystectomy in women.
Am J Med. 2006 Sep;119(9):760-7.

Vakhrushev IaM, Suchkova EV.
Use of essentiale and cholagogum in prevention of cholelithiasis in fat hepatosis with concomitant cholecystitis 
Ter Arkh. 2005;77(2):18-21.

von Bergmann K, Beck A, Engel C, Leiss O.
Administration of a terpene mixture inhibits cholesterol nucleation in bile from patients with cholesterol gallstones.
Klin Wochenschr. 1987 May 15;65(10):458-62.

Walcher T, Haenle MM, Kron M, Hay B, Mason RA, Walcher D, Steinbach G, Kern P, Piechotowski I, Adler G, Boehm BO, Koenig W, Kratzer W; EMIL study group.
Vitamin C supplement use may protect against gallstones: an observational study on a randomly selected population.
BMC Gastroenterol. 2009 Oct 8;9:74.

Weinsier RL, Ullmann DO.
Gallstone formation and weight loss.
Obes Res. 1993 Jan;1(1):51-6.

Williams CA, Goldstone F, Greenham J.
Flavonoids, cinnamic acids and coumarins from the different tissues and medicinal preparations of Taraxacum officinale.
Phytochemistry. 1996 May;42(1):121-7.

Wright, Jonathan V.
The 99.9 percent effective technique for eliminating gallbladder attacks forever
Nutrition and Healing. 2004; 11(9):1

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Kidney Stones: The Basics

green-healthy-foodUreterolithiasis, renal calculi, nephrolithiasis and kidney stone all mean the same thing:  agony.  The nurse told us the pain is equivalent to passing a five-pound canned ham through the southern end of the digestive system, with the lid opened.  If you’ve never experienced the long road to relief, thank the Creator for being excused.

What causes kidney stones?

There is no single cause, but a combination of factors.  The wrong balance of fluids, minerals and acids can put you on your knees faster than being knighted.  If urine has more crystal-making elements than the fluid can dilute, bingo, you have the makings of a stone…or stones.  In looking for a definitive cause, science has left no stone unturned.  No pun intended.  Beneath one of those stones is fluoride, having been fingered as causative a decade ago, but only in those with symptoms of skeletal fluorosis and the propensity to form stones in the first place (Singh, 2001).  That rules lots of us out.  Whether or not high doses of vitamin C are implicated in the formation of stones is debatable and based on the status of other nutrients.  By itself, vitamin C, chemically known as ascorbic acid, is able to be converted by the body into oxalates, which increases the likelihood of making oxalate stones among stone formers who take more than the recommended upper limit of 2000 mg of vitamin C a day (Massey, 2005). But you gotta be a stone former.  Is that like a mason?   Earlier research found that high intake of vitamin B6, pyridoxine, reduces the risk of stone formation from unrestricted doses of ascorbic acid (Curhan, 1999).   Up to 500 mg of pyridoxine a day was found to be useful in the control of elevated urinary oxalates (Mitwali, 1988).  In a study reported in the New England Journal of Medicine in the dark ages of the last century, the degree of oxaluria dictates the dosage of vitamin B6.  But the degree of supplementation depends on how much B6 comes from food (Yendt, 1985).

What are they made from?

Most stones (~80%) are calcium oxalate calculi, which crystallizes in a hurry.  It’s the stuff that forms a needle-like crust on the inside of a brewery container.  If you swallowed this material, you’d get really sick, and maybe die.  Calcium oxalate crystal formation is one of the effects of ingesting antifreeze.  A small dose of calcium oxalate will make your tongue burn and swell your throat shut.  This is what happens when the cat chews on a Dieffenbachia leaf in the living room window, and then requires a trip to the vet.

Some plants, including spinach, contain calcium oxalate in their leaves. If you’re a stone former, you might choose to avoid, or at least limit, raw spinach salads, although some researchers say it doesn’t matter, as long as you’re amply hydrated and your diet is sufficiently balanced to provide calcium and vitamin B6, both of which are found in spinach (Curhan, 1999).  A little baffling, huh?  After a stone passes through the urine and gets collected in that little strainer that painters use to get the globs out of a gallon of linen white, you’ll be asked to take that stone to the doctor so he can determine its makeup.  Then he’ll know what course of action to give you.

How do I prevent kidney stones?

If ever the proverbial ounce of prevention is worth a lot, this is the place.  Most experts agree that drinking fluids is the key.  Believe us when we say that a stone former is more than willing to increase his water intake, despite its lack of flavor.  If you need flavor, try lemon juice.  Counseling in this area is simple:  if you don’t drink enough water, you’ll experience this again.  That means you have to drink even when you’re not thirsty (McCauley, 2012).  Swapping soft drinks for water is prudent (Fink, 2009).

Increasing dietary calcium intake is inversely related to stone formation.  Supplemental calcium, on the other hand, may increase risk.  Dietary calcium blocks the amount of oxalates absorbed by the body, while supplements, especially if taken between meals, spill too much of the mineral into the urine.  If calcium supplementation is needed, take it with a meal to improve absorption.  We’re cautioned not to take more than 500 mg at a time, anyway.  It’s all about the timing (Curhan, 1997).

It’s believed that most stones form in the summer, when people are more likely to get dehydrated, so we’re admonished to drink ten to twelve glasses of water a day.  Other beverages, though, fare well in the prevention category.  Caffeinated and decaffeinated coffee, tea, and wine accounted for a decreased risk of stone formation, according to the Brigham and Women’s Hospital study of the 1990’s (Curhan, 1998).

Obesity increases the risk of kidney stones, but drastic weight loss measures that rely on high protein intake can stymie the good intentions.  So, too, can laxative abuse, rapid loss of lean tissue and, naturally, poor hydration.  A diet high in fruits and vegetables can alkalize urine enough to offset oxalate and uric acid stone formation ( Frassetto, 2011).  Produce is known for its magnesium content.  Intake of magnesium is related to reduced stone manufacture, and has been a recommendation since the 17th century.  Even without overt deficiency, magnesium intake, at 500 mg a day in the form of magnesium hydroxide, was shown to decrease stone formation, and it has no adverse side effects as long as it’s not overzealously done (Johansson, 1980 and 1982).  Too much magnesium may induce laxation.  That’s an individual response.   Later study learned that magnesium combined with vitamin B6 offered a substantial decline in the risk for oxalate stones (Rattan, 1994)

Kale, turnip greens, radishes, chard and other leafy greens, broccoli, Brussels sprouts, and cabbage are good sources of dietary calcium.  Almonds and cashews, pumpkin seeds, barley, quinoa, leafy greens, white and black beans are a few good sources of magnesium.  Since calcium and magnesium compete for occupancy in the body, with calcium the winner, magnesium supplementation is a good idea.  An Epsom salts bath allows magnesium levels to increase transdermally…and it’ll help you fall asleep.  Drink water.  Prevent stones.


Conte A, Pizá P, García-Raja A.
Urinary lithogen risk test: usefulness in the evaluation of renal lithiasis treatment using crystallization inhibitors (citrate and phytate).
Arch Esp Urol. 1999 Jan-Feb;52(1):94-9.

Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ.
Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women.
Ann Intern Med. 1997 Apr 1;126(7):497-504.

Curhan GC, Willett WC, Speizer FE, Stampfer MJ.
Beverage use and risk for kidney stones in women.
Ann Intern Med. 1998 Apr 1;128(7):534-40

Curhan GC, Willett WC, Speizer FE, Stampfer MJ.
Intake of vitamins B6 and C and the risk of kidney stones in women.
J Am Soc Nephrol. 1999 Apr;10(4):840-5.

Curhan GC.
Epidemiologic evidence for the role of oxalate in idiopathic nephrolithiasis.
J Endourol. 1999 Nov;13(9):629-31.

Fink HA, Akornor JW, Garimella PS, MacDonald R, Cutting A, Rutks IR, Monga M, Wilt TJ.
Diet, fluid, or supplements for secondary prevention of nephrolithiasis: a systematic review and meta-analysis of randomized trials.
Eur Urol. 2009 Jul;56(1):72-80. Epub 2009 Mar 13.

Frassetto L, Kohlstadt I.
Treatment and prevention of kidney stones: an update.
Am Fam Physician. 2011 Dec 1;84(11):1234-42.

Gill HS, Rose GA.
Mild metabolic hyperoxaluria and its response to pyridoxine.
Urol Int. 1986;41(5):393-6.

Grases F, Costa-Bauzá A.
Phytate (IP6) is a powerful agent for preventing calcifications in biological fluids: usefulness in renal lithiasis treatment.
Anticancer Res. 1999 Sep-Oct;19(5A):3717-22.

Habbig S, Beck BB, Hoppe B.
Nephrocalcinosis and urolithiasis in children.
Kidney Int. 2011 Dec;80(12):1278-91. doi: 10.1038/ki.2011.336. Epub 2011 Sep 28.

Johansson G, Backman U, Danielson BG, Fellström B, Ljunghall S, Wikström B.
Biochemical and clinical effects of the prophylactic treatment of renal calcium stones with magnesium hydroxide.
J Urol. 1980 Dec;124(6):770-4.

Johansson G, Backman U, Danielson BG, Fellström B, Ljunghall S, Wikström B.
Effects of magnesium hydroxide in renal stone disease.
J Am Coll Nutr. 1982;1(2):179-85.

Massey LK, Liebman M, Kynast-Gales SA.
Ascorbate increases human oxaluria and kidney stone risk.
J Nutr. 2005 Jul;135(7):1673-7.

McCauley LR, Dyer AJ, Stern K, Hicks T, Nguyen MM.
Factors influencing fluid intake behavior among kidney stone formers.
J Urol. 2012 Apr;187(4):1282-6. Epub 2012 Feb 15.

Miggiano GA, Migneco MG.
[Diet and nutrition in nephrolitiasis].   [Article in Italian]
Clin Ter. 2007 Jan-Feb;158(1):49-54.

Mitwalli A, Ayiomamitis A, Grass L, Oreopoulos DG.
Control of hyperoxaluria with large doses of pyridoxine in patients with kidney stones.
Int Urol Nephrol. 1988;20(4):353-9.

Moyad MA.
Calcium oxalate kidney stones: another reason to encourage moderate calcium intakes and other dietary changes.
Urol Nurs. 2003 Aug;23(4):310-3.

Rattan V, Sidhu H, Vaidyanathan S, Thind SK, Nath R.
Effect of combined supplementation of magnesium oxide and pyridoxine in calcium-oxalate stone formers.
Urol Res. 1994;22(3):161-5.

Saxena A, Sharma RK.
Nutritional aspect of nephrolithiasis.
Indian J Urol. 2010 Oct;26(4):523-30.

Singh PP, Barjatiya MK, Dhing S, Bhatnagar R, Kothari S, Dhar V.
Evidence suggesting that high intake of fluoride provokes nephrolithiasis in tribal populations.
Urol Res. 2001 Aug;29(4):238-44.

Yendt ER, Cohanim M.
Response to a physiologic dose of pyridoxine in type I primary hyperoxaluria.
N Engl J Med. 1985 Apr 11;312(15):953-7.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Good News About Coffee

cup-of-coffee-on-saucerThe inveterate coffee drinkers among us will appreciate the good news about one of our favorite beverages. After all the flak we took about the vices of coffee, now’s the chance to respond. After water and tea, coffee is the next most popular drink on the planet, having a starring role in the history of several cultures. It came from the Muslim world, travelled to Italy and then to the rest of Europe, finally landing in the New World. At one time, it was limited only to religious observances.

The coffee bean is contained inside a “cherry” that grows on a small evergreen bush.  The Arabica strain is the more highly regarded of the two chief varieties, but the robusta strain is more resistant to the diseases peculiar to this plant, though less flavorful and more bitter. Arabica prefers the coolness of the mountainside; robusta will grow at lower elevations and in warmer climates. Since the best tasting coffee really is mountain grown, the sales talk of a particular brand is true. But Mrs. Olsen never told us that other brands also use mountain grown beans. She merely capitalized on a little-known fact.

One effect of coffee consumption is moderately elevated blood pressure, which is not surprising because caffeine is a stimulant. Italian studies done in the early 1990’s found that 200 milligrams of caffeine, about two cups’ worth, could raise systolic blood pressure by 10% and diastolic by 5% for up to two hours after consumption. The mechanism points to vasoconstriction (which has its own benefits), but researchers found no variation in heart rate or cardiac contractility (Casiglia, 1991), leading to an assumption that this temporary state is not a major concern, especially in light of later studies that reported no association between long-term coffee consumption and increase of cardiovascular complications (Mesas, 2011) or risk of hypertension (Geleijnse, 2008) (Klag, 2002).

Vitamin B6, known as pyridoxine, is a nutrient occasionally used to tame morning sickness in pregnancy and the throes of PMS. It’s also been used to address homocysteine imbalance, carpal tunnel syndrome, immunity deficiencies, and various behavioral/psychiatric issues. However, careless dosing of vitamin B6 can cause medical concerns that outweigh the benefits of producing the monoamine neurotransmitters, serotonin and dopamine. Large doses of B6 over a period of time can cause nerve fiber damage, particularly auditory neuropathy. You’d never think that coffee can prevent and treat this malady, but it does (Hong, 2008). One active coffee component is called trigonelline (Hong, 2009), an alkaloid also found in pumpkin that is able to modulate blood glucose (van Dijk, 2009) (Yoshinari, 2009). Because auditory neuropathy may be attenuated by trigonelline, why can’t the peripheral neuropathy of diabetes or physical trauma likewise be eased? It’s worth a look (Zhou, 2012).

Late-life dementia and Alzheimer’s disease (AD) are concerns shared by an aging population across the globe. Finnish studies followed a number of middle-agers for more than twenty years, documenting their coffee (and tea) consumption along the way.  Focusing more on caffeine than on coffee’s lesser-known constituents, researchers found that, over the long haul, those who drank three to five cups of coffee a day at midlife had a lower risk of dementia and AD in old age (Eskelinen, 2009, 2010).  American studies later found that long-term coffee consumption protects against cognitive impairment by reducing the formation of amyloid beta, the protein that forms the plaques associated with AD. Here it was inferred that caffeine is part of a synergy that affords the desired effect, with many coffee constituents not yet identified (Cao, 2011).

Because early research had indicated that coffee may be protective against conditions other than neurological, scientists took the trigonelline link a little further. It’s accepted that people with diabetes are at risk for cognitive dysfunction. Initially, it was proposed that coffee was merely to be explored as a tool in the management of diabetes and related sequelae (Biessels, 2010). It was realized, however, that caffeine can decrease the risk of type 2 diabetes and consequent cognitive decline (Salazar-Martinez, 2004) (Tuomilehto, 2004).

In general, coffee increases plasma antioxidant capacity, possibly because of the contribution, bioavailability and activity of its particular group of polyphenols, including chlorogenic acid, one component linked to a reduction of type 2 diabetes risk by virtue of delaying intestinal glucose absorption and the inhibition of gluconeogenesis (Ong, 2010) (Tunnicliffe, 2011). Other medical conditions are purported to be influenced by coffee’s mechanisms, including gastrointestinal diseases (Inoue, 1998), gallstones (Leitzmann, 1999), and Parkinson’s disease (Checkoway, 2002) (Blanchette, 2000).

If coffee has a down side, it’s that it can interact with some drugs, most notably quinolone antibiotics, such as ciprofloxacin and its kin, which increase caffeine concentrations by inhibiting its clearance (Harder, 1989). Coffee’s popularity cannot be ignored. Just look at all the coffee options that run the gamut from hot to cold, from sweet to sweeter, and from low-cal to mega-cal. Since the 1989 expiration of a global agreement to stabilize supply, availability has fluctuated—and so has the price. You can’t even get the cup for a dime any more.


Biessels GJ.
Caffeine, diabetes, cognition, and dementia.
J Alzheimers Dis. 2010;20 Suppl 1:S143-50.

Campdelacreu J.
Parkinson disease and Alzheimer disease: environmental risk factors.
[Article in English, Spanish]

Neurologia. 2012 Jun 13. [Epub ahead of print]

Cao C, Wang L, Lin X, Mamcarz M, Zhang C, Bai G, Nong J, Sussman S, Arendash G.
Caffeine synergizes with another coffee component to increase plasma GCSF: linkage to cognitive benefits in Alzheimer’s mice.
J Alzheimers Dis. 2011;25(2):323-35.

Casiglia E, Bongiovì S, Paleari CD, Petucco S, Boni M, Colangeli G, Penzo M, Pessina AC.
Haemodynamic effects of coffee and caffeine in normal volunteers: a placebo-controlled clinical study.
J Intern Med. 1991 Jun;229(6):501-4.

Checkoway H, Powers K, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD.
Parkinson’s disease risks associated with cigarette smoking, alcohol consumption, and caffeine intake.
Am J Epidemiol. 2002 Apr 15;155(8):732-8.

Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M.
Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study.
J Alzheimers Dis. 2009;16(1):85-91.

Eskelinen MH, Kivipelto M.
Caffeine as a protective factor in dementia and Alzheimer’s disease.
J Alzheimers Dis. 2010;20 Suppl 1:S167-74.

Floegel A, Pischon T, Bergmann MM, Teucher B, Kaaks R, Boeing H
Coffee consumption and risk of chronic disease in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany study.
Am J Clin Nutr. 2012 Apr;95(4):901-8.

Yoichi Fukushima, Takashi Ohie, Yasuhiko Yonekawa, Kohei Yonemoto, Hiroki Aizawa, Yoko Mori, Makoto Watanabe, Masato Takeuchi, Maiko Hasegawa, Chie Taguchi and Kazuo Kondo
Coffee and Green Tea As a Large Source of Antioxidant Polyphenols in the Japanese Population
Journal of Agricultural and Food Chemistry 2009 57 (4), 1253-1259

Gelber RP, Petrovitch H, Masaki KH, Ross GW, White LR.
Coffee intake in midlife and risk of dementia and its neuropathologic correlates.
J Alzheimers Dis. 2011;23(4):607-15.

Geleijnse JM.
Habitual coffee consumption and blood pressure: an epidemiological perspective.
Vasc Health Risk Manag. 2008;4(5):963-70.

Harder S, Fuhr U, Staib AH, Wolff T.
Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations.
Am J Med. 1989 Nov 30;87(5A):89S-91S.

Head KA.
Peripheral neuropathy: pathogenic mechanisms and alternative therapies.
Altern Med Rev. 2006 Dec;11(4):294-329.

Hermansen K, Krogholm KS, Bech BH, Dragsted LO, Hyldstrup L, Jørgensen K, Larsen ML, Tjønneland AM.
Coffee can protect against disease
Ugeskr Laeger. 2012 Sep 24;174(39):2293-2297.

Hong BN, Yi TH, Park R, Kim SY, Kang TH.
Coffee improves auditory neuropathy in diabetic mice.
Neurosci Lett. 2008 Aug 29;441(3):302-6. Epub 2008 Jun 22.

Hong BN, Yi TH, Kim SY, Kang TH.
High-dosage pyridoxine-induced auditory neuropathy and protection with coffee in mice.
Biol Pharm Bull. 2009 Apr;32(4):597-603.

Huxley R, Lee CM, Barzi F, Timmermeister L, Czernichow S, Perkovic V, Grobbee DE, Batty D, Woodward M.
Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus: a systematic review with meta-analysis.
Arch Intern Med. 2009 Dec 14;169(22):2053-63.

Inoue M, Tajima K, Hirose K, Hamajima N, Takezaki T, Kuroishi T, Tominaga S.
Tea and coffee consumption and the risk of digestive tract cancers: data from a comparative case-referent study in Japan.
Cancer Causes Control. 1998 Mar;9(2):209-16.

Kaiser permanante Division of Research
Coffee Drinking and Caffeine Associated with Reduced Risk of Hospitalization for Heart Rhythm Disturbances

Klag MJ, Wang NY, Meoni LA, Brancati FL, Cooper LA, Liang KY, Young JH, Ford DE.
Coffee intake and risk of hypertension: the Johns Hopkins precursors study.
Arch Intern Med. 2002 Mar 25;162(6):657-62.

Leitzmann MF, Willett WC, Rimm EB, Stampfer MJ, Spiegelman D, Colditz GA, Giovannucci E.
A prospective study of coffee consumption and the risk of symptomatic gallstone disease in men.
JAMA. 1999 Jun 9;281(22):2106-12.

Mesas AE, Leon-Muñoz LM, Rodriguez-Artalejo F, Lopez-Garcia E.
The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis.
Am J Clin Nutr. 2011 Oct;94(4):1113-26. Epub 2011 Aug 31.

Oba S, Nagata C, Nakamura K, Fujii K, Kawachi T, Takatsuka N, Shimizu H.
Consumption of coffee, green tea, oolong tea, black tea, chocolate snacks and the caffeine content in relation to risk of diabetes in Japanese men and women.
Br J Nutr. 2010 Feb;103(3):453-9. Epub 2009 Oct 12.

Ong KW, Hsu A, Tan BK.
Chlorogenic acid stimulates glucose transport in skeletal muscle via AMPK activation: a contributor to the beneficial effects of coffee on diabetes.
PLoS One. 2012;7(3):e32718. Epub 2012 Mar 7.

Richelle M, Tavazzi I, Offord E.
Comparison of the antioxidant activity of commonly consumed polyphenolic beverages (coffee, cocoa, and tea) prepared per cup serving.
J Agric Food Chem. 2001 Jul;49(7):3438-42.

Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, Tanner CM, Masaki KH, Blanchette PL, Curb JD, Popper JS, White LR.
Association of coffee and caffeine intake with the risk of Parkinson disease.
JAMA. 2000 May 24-31;283(20):2674-9.

Salazar-Martinez E, Willett WC, Ascherio A, Manson JE, Leitzmann MF, Stampfer MJ, Hu FB.
Coffee consumption and risk for type 2 diabetes mellitus.
Ann Intern Med. 2004 Jan 6;140(1):1-8.

Tunnicliffe JM, Eller LK, Reimer RA, Hittel DS, Shearer J.
Chlorogenic acid differentially affects postprandial glucose and glucose-dependent insulinotropic polypeptide response in rats.
Appl Physiol Nutr Metab. 2011 Oct;36(5):650-9. Epub 2011 Oct 6.

Tuomilehto J, Hu G, Bidel S, Lindström J, Jousilahti P.
Coffee consumption and risk of type 2 diabetes mellitus among middle-aged Finnish men and women.
JAMA. 2004 Mar 10;291(10):1213-9.

van Dijk AE, Olthof MR, Meeuse JC, Seebus E, Heine RJ, van Dam RM.
Acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance.
Diabetes Care. 2009 Jun;32(6):1023-5. Epub 2009 Mar 26.

Yoshinari O, Sato H, Igarashi K.
Anti-diabetic effects of pumpkin and its components, trigonelline and nicotinic acid, on Goto-Kakizaki rats.
Biosci Biotechnol Biochem. 2009 May;73(5):1033-41. Epub 2009 May 7.

Zhou J, Chan L, Zhou S.
Trigonelline: a plant alkaloid with therapeutic potential for diabetes and central nervous system disease.
Curr Med Chem. 2012 Jul 1;19(21):3523-31.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.