Studies Confirm: Natural and Synthetic Vitamins Can Differ in Quantity & Quality of Effects! Vitamins A-E, B's & More

Pills or fruits, one are funky and useless, the other ancient and healthy!?

In a 2000 paper in Medical Hypothesis, R.J. Thiel writes "[t]here appears to be a tendency to label those who profess that natural vitamins are better than synthetic ones as quacks" (Thiel. 2000). No wonder, after all, every good text book will inform future physicians and researchers that the difference between natural and synthetic alpha-tocopherol was a mere quantitative one.

In other words, as long as you make sure that you administer 1.36x the amount of "natural" vitamin E in,   all-rac-α-tocopherol should do the exact same as its natural cousin.

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Even common sense, should tell us, though, that it is unlikely that a colorful mix of  four vitamin E stereoisomers (SRR, SRS, SSR, and SSS) won't have the same effect as pure RRR-alpha-tocopherol as it can be found in nature. Accordingly, Thiel may be right, when he writes that "[t]his broad brush label may be stifling legitimate nutrition research" (Thiel. 2000). In his paper he addresses several issues, including the often heard claim that the body cannot distinguish between natural and synthetic forms of vitamin E, a claim of which he argues that it is misleading because

• it neglects the effect of different structures on absorption and utilization of vitamins (Schumann. 1997; Vinson. 1988, 1989 & 1999);
• it ignores the size differences between the various isomers that will directly affect the absorption of and bioavailability of the nutrients (Macrae. 1993); 
• it does not seem to consider the fact that "natural" vitamins in the original sense come in a nutrient matrix that will have profound effects on both the absorption & activity and the effects of vitamin E containing foods (and complex supplements | Jenkins. 1994);
• it ignores the fact that most USP vitamins are crystalline in structure (Ensminger. 1993; Macrae. 1993), while most vitamins in food are not (and are actually present in complex carbohydrates, proteins, and lipids | Thiel. 1999)

All this  does not mean that USP vitamins do not have any value (they clearly do), but studies have shown that vitamins in natural food complexes are better than USP isolated vitamins; and here is a handful of examples:

• Vitamin A - As it is the case for many other vitamins, the term vitamin A refers to a whole class of molecules, called "retinoids", which include both retinol and its natural metabolites as well as a large number of synthetic analogues that have structural similarities to retinol but may subserve only some (or none) of the functions of natural vitamin A (Ross. 1999).
  
  

  

  Neural tube & other defects increase sign. w/ high doses of synthetic, but not food-borne natural retinol (Rothman. 1995).

  As Thiel points out, some of the commonly used forms found in synthetic supplements are not naturally found in food (Ross. 1999). Some of them have been linked to liver cirrhosis (Fallon. 1990). More specifically, it has been reported that consumption of more than 10 000 I.U. per day of synthetic vitamin A increased the rate of birth defects, while consumption of natural vitamin A from foods (including betacarotene, a precursor) did not (Rothman. 1995).
  
  Retinyl acetate is the major synthetic form of vitamin A and is a vinyl or coal tar at one or more stages of processing (depending upon the manufacturer) (Hu. 1992). An animal study found that synthetic vitamin A in the form of retinyl acetate significantly reduced vitamin E utilization (Schelling. 1995); this has not been shown to occur with natural vitamin A (i.e. Ross. 1999). An animal study concluded that a natural food complex vitamin A was probably less toxic than a synthetic USP form and was 1.54 times more absorbed into the blood (Vinson. 1989).

Please note: Most of the differences are of quantitative nature, which means that you will have to take more of the "synthetic" version to achieve similar steady state levels. Only in some cases, the effects are qualitatively different. However, in some genetically disadvantaged individuals, who cannot do the conversion that is necessary for e.g. folic acid or pyridoxin (B6), these differences can be qualitative (because the agents don't work at all or, as in the case of folic acid) even break the whole system.

• Thiamin, Vitamin B1 - The free vitamin B1 (called thiamin) is a base. When it is synthesized it becomes a solid salt such as thiamin hydrochloride or thiamin mononitrate (Tanphaichitr. 1994). Synthetically thiamin is usually marketed as thiamin hydrochloride or thiamin mononitrate and is a made from Grewe diamine (a coal tar derivative) processed with ammonia and other chemicals (Hui. 1992). No thiamin hydrochloride (often listed as thiamin HCL) or thiamin mononitrate is naturally found in food or the body (thiamin pyrophos phate is the predominant form in the body (Tanphaichitr. 1994))).
  
  Against that background it's not surprising that an animal study found that a natural food complex vitamin B1 was absorbed 1.38 times more into the blood and was retained 1.27 times more in the liver than an isolated USP thiamin hydrochloride (Vinson. 1989).
• Riboflavin, Vitamin B2 - The free vitamin B2 (called riboflavin) is a weak base. When synthesized it becomes an orange amorphous solid. Some synthetic riboflavin analogues have very weak vitaminic activity (Kanno. 1991).
  
  Animal studies indicate that a natural food complex vitamin B2 was absorbed into the blood and was retained 1.92 times more in the liver than an isolated USP riboflavin (Vinson. 1989).
• Niacinamide, Vitamin B3 - ‘Niacin is a generic term, the two coenzymes that are the metabolically active forms of niacin (are) nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP).
  
  

  

  Peas, peanut(butter), poultry, ... if it starts with "p" it's a good source of niacin ;-)

  Only small amounts of free forms of niacin occur in nature. Most of the niacin in food is present as a component of NAD and NADP nicotinamide is more soluble in water, alcohol, and ether than nicotinic acid. Beef, legumes, cereal grains, yeast, and fish are significant natural food sources of vitamin B3, of which studies indicate that it has a 3.94 times higher absorption rate than synthetic B3 and will be retained 1.7 times more efficiently in the liver than isolated USP niacinamide (Vinson. 1989).
• Pyridoxine, Vitamin B6 - Just like B2 & B3, the USP "vitamin B6", pyridoxine is not the naturally occuring form of the vitamin. It is thus not surprising that the absorption of the "original" is 2.54 times more into the blood and its retention in the liver is 1.56 times higher compared to the USP form (Vinson. 1989).
• Folate, Vitamin B9 - Is one of the few vitamins where many experts acknowledge that its use as a dietary supplement is bogus. No wonder, pteroylglutamic acid, the common pharmacological (USP) form known as folic acid, is not found significantly as such in the body and appears to be absorbed differently than folate (Herbert. 1999). Folic acid is not found in foods, but folate is (23). Herbert reports a study found ‘that consumption of more than 266 mg of synthetic folic acid (PGA) results in absorption of unreduced PGA, which may in fact interfere with folate metabolism for a period of years’ (Herbert. 1999).
  
  Against that backround the fact that the natural food complex folate is absorbed only 1.07 times more into the blood, yet retained 2.13 times more in the liver than isolated USP folic acid (Vinson. 1989) appears less important than the potential interference of excess folic acid intakes with the metabolism of "true" folate which has been shown to trigger liver fibrosis (Marsillach. 2008) and is associated with the development and progression of cancer (with the exception of colorectal cancer | Kim. 2008; Ulrich. 2006).
• Vitamin C, ascorbic acid - The name gives it away, there is no chemical difference between "natural" and "synthetic" vitamin C; it's both plain ascorbic acid. What is missing if you get your vitamin C in pill instead of apple, citrus-fruit and other food-born forms are yet
  the active form of vitamin C, dehydroascorbic acid (DHAA), and its natural synergists which are required for vitamin C to work optimally.
  
  Studies have shown that the "bioavailability of vitamin C in food and 'natural form' supplements is not significantly different from that of pure synthetic AA" (10) which is true, when we look at ascorbic acid in isolation like Mangels et al. (Mangels. 1993) did.
  

  

  Mangels et al. compared the rate (dVit-C/dt), i.e. the slope of the graphs that depict the repletion rates after an 8-week cycle on a vitamin C deficient diet for various forms of vitamin C (Mangels. 1993).

  Mangels et al. did yet ignore the individual and synergistic effects of DHAA or other food constituents associated with natural vitamin C which may have positive effects other than raising serum ascorbate levels. Preliminary data from Vinson et al. (1988) however suggests that vitamin C complexed in food is absorbed 1.74 times more into red blood cells than isolated USP  ascorbic acid, while another found it to be 1.35 times more absorbed into the plasma.
  
  A result that leaves no doubt that simple serum vitamin C measurements as they are done in most studies may be insufficient to identify the subtle advantages of natural vitamin C which does not come in pill form (don't believe the supplement companies claiming they used "natural vitamin C" had figured out what you need to imitate nature).
• Vitamin D - While it has not been proven that any single USP isolated form of vitamin D has all the benefits as natural occurring forms of vitamin D, there is also insufficient evidence that the currently (over-)hyped vitamin D3 supplements alone would be insufficient and should be replaced by something like a "natural full spectrum vitamin D supplement".
  

  

  25OHD content (µg/100g) of chicken & egg, pork, beef, fish, dairy (various sources; more)

  One thing to keep in mind, though, is the fact that there is more to vitamin D than D3; naturally high vitamin D foods like eggs, for example, are "high vitamin D foods" that contain, among other isoforms of vitamin D, also the already active form calcitriol and may thus have a significantly more pronounced health benefit than powders, caps and pills. 
• Vitamin E - As SuppVersity reader you know that supplemental alpha-tocopherol pills have little to do with the full spectrum of tocopherols and trienols foods have to offer.
  
  I have written about this in the past so extensively that I don't want to explain everything for the 10414th time. So, if you are interested in tocotrienols and tocopherols, browse the archive. What I would like to focus on, today, is the difference between synthetic and natural alpha-tocopherol. What is undebated is the that synthetic vitamin E is mixture of eight epimers’, while natural alpha-tocopherol contains only the [d]-epimer of alpha-tocopherol (9). As Thiel points out in his review, the existing evidence clearly

  "indicates that although synthetic vitamins have some of the benefits of natural vitamins, they really do not replace all the benefits of natural ones" (Thiel. 2000).

  This is not surprising, since un foods, natural vitamin E is always found with lipids and other food substances of which Acuff et al. that it is absorbed 3.42 times better than synthetic vitamin E in cord blood during pregnancy.
  
  

  

  The higher urinary excretion of synthetic (d₆) vs. natural (d₃) vitamin E suggests that the human body wants to get rid of the synthetic mix (Traber. 1998).

  Similar results have been observed in rodents, where vitamin E complexed in foods was 2.6 times more retained than isolated USP d-alpha tocopheryl acid succinate (which is the so-called ‘natural form’ once it is isolated from its food complex | Venson. 1989). Results that are in line with observations, Traber et al. made, when they studied human urine and fount that natural vitamin E was not only 2.7 times better absorbed than synthetic vitamin E, but that the body may want to rid itself of the synthetic as quickly as possible (Traber. 1998). 

Bottom line: If you briefly recap the previously reported results, it appears as if the divide between natural and synthetic was less pronounced than some bullocks-website would have it. On the other hand, the often-heard claim that natural and synthetic vitamins were identical is questionable and in some cases like folic acid, vitamin E and others simply false.

One of the reasons we even have to worry about adequate vitamin intakes despite living in abundance, is the quality of our foods (or rather their lack of quality). Food processing techniques can reduce the amount of every known essential vitamin. The refining of rice reduce B-complex vitamins and initially led to deaths in Asia due to beriberi. And even if synthetic USP vitamins are added to white rice, it does not contain the same nutrients as unpolished brown rice (nor does white
flour contain the same nutrients as whole flour).

The reductions in liver vitamin A + E in pigs fed diets containing the fat substitute Olestra and identical amounts of synthetic vits what happens when we replace natural vitamin (Daher. 1997).

"The refining of whole grains (including wheat, rice, and corn) has resulted in a dramatic reduction of their natural food complex nutrients. The milling of wheat to white flour reduces the natural food complex vitamin and mineral content by 40–60%. Various food processing techniques (including pasteurization of milk) reduce the available vitamin B6 in foods by 10–50%. The recently introduced artificial fat olestra (also known as Olean) robs the body of oil soluble vitamins (vitamins A, D, E, and K) and carotenoid antioxidants (betacarotene, lutein, lycopene) [...] Irradiation of meat and other foods ‘changes the characteristics of food’ and has been found to reduce levels of vitamins A, B1, B6, E, K, and other nutrient levels" (Thiel. 2000).

The list could and will be continued, after all it appears to be certain that hitherto unknown nutrients will also be affected from food processing; and even if we found all of them and replaced them with USP isolates it is, we cannot be sure that the effects would be better than for some of the previously discussed vital nutrients. Against that background you don't have to be "paleo" to ask yourself if the synthetically enhanced foods will ever offer all, or even almost all of the health benefits the original unprocessed foods have | Comment on Facebook!

References:

• Acuff, Robert V., et al. "Transport of deuterium-labeled tocopherols during pregnancy." The American journal of clinical nutrition 67.3 (1998): 459-464.
• Daher, George C., Dale A. Cooper, and John C. Peters. "Physical or temporal separation of olestra and vitamins A, E and D intake decreases the effect of olestra on the status of the vitamins in the pig." The Journal of nutrition 127.8 (1997): 1566S-1572S.
• Ensminger A. H., Ensminger M. E., Konlade J. E., Robson J. R. K. Food & Nutrition Encyclopedia, 2nd ed. New York: CRC Press, 1993.
• Fallon, Michael B., And James L. Boyer. "Hepatic toxicity of vitamin A and synthetic retinoids." Journal of gastroenterology and hepatology 5.3 (1990): 334-342.
• Herbert, Victor, and K. C. Das. "Folic acid and vitamin B12." Modern nutrition in health and disease 1 (1994): 402-25.
• Herbert V. Folic Acid In Modern Nutrition in Health and Disease, 9th ed. Baltimore: William & Wilkins, 1999: 433–446.
• Hui J. H. Encyclopedia of Food Science and Technology. New York: John Wiley, 1992.
• Jenkins, D. J. A., T. M. S. Wolever, and A. L. Jenkins. "Diet factors affecting nutrient absorption and metabolism." Modern nutrition in health and disease 8 (1994): 583-602.
• Kanno, Choemon, et al. "Binding form of vitamin B2 in bovine milk: Its concentration, distribution and binding linkage." Journal of nutritional science and vitaminology 37.1 (1991): 15-27.
• Kim, Young-In. "Folic acid supplementation and cancer risk: point." Cancer Epidemiology Biomarkers & Prevention 17.9 (2008): 2220-2225.
• Macrae R., Robson R. K., Sadler M. J. Encyclopedia of Food Science and Nutrition. New York: Academic Press, 1993. 
• Mangels, Ann R., et al. "The bioavailability to humans of ascorbic acid from oranges, orange juice and cooked broccoli is similar to that of synthetic ascorbic acid." The Journal of nutrition 123.6 (1993): 1054-1061.
• Marsillach, Judit, et al. "Moderately high folic acid supplementation exacerbates experimentally induced liver fibrosis in rats." Experimental Biology and Medicine 233.1 (2008): 38-47.
• Ross A. C. Vitamin A and retinoids. In Modern Nutrition in Health and Disease, 9th ed. Baltimore: William & Wilkins, 1999: 305–327.
• Rothman, Kenneth J., et al. "Teratogenicity of high vitamin A intake." New England Journal of Medicine 333.21 (1995): 1369-1373.
• Schelling, Gerald T., et al. "Bioavailability and interaction of vitamin A and vitamin E in ruminants." The Journal of nutrition 125.6 Suppl (1995): 1799S-1803S.
• Schumann, K, et al.  "Bioavailability of oral vitamins, minerals, and trace minerals in perspective". Arzneimittelforschung, 47 (1997), pp. 369–38.
• Tanphaichitr V. Thiamin. In Modern Nutrition in Health and Disease, 8th ed. Philadelphia: Lea & Febiger, 1994: 359–365.
• Thiel, R. "Vitamins are naturally found in food complexes." ANMA Monito 3.1 (1999): 5-9.
• Traber, Maret G., Angelika Elsner, and Regina Brigelius-Flohé. "Synthetic as compared with natural vitamin E is preferentially excreted as α-CEHC in human urine: studies using deuterated α-tocopheryl acetates." FEBS letters 437.1 (1998): 145-148.
• Ulrich, Cornelia M., and John D. Potter. "Folate supplementation: too much of a good thing?." Cancer Epidemiology Biomarkers & Prevention 15.2 (2006): 189-193.
• Vinson, Joe A., and Pratima Bose. "Comparative bioavailability to humans of ascorbic acid alone or in a citrus extract." The American journal of clinical nutrition 48.3 (1988): 601-604.
• Vinson J., Bose P., Lemoine L., Hsiao K. H. "Bioavailability studies". In Nutrient Availability: Chemical and Biological Aspects. Cambridge (UK): Royal Society of Chemistry, 1989: 125–127.
• Vinson, Joe A., et al. "A citrus extract plus ascorbic acid decreases lipids, lipid peroxides, lipoprotein oxidative susceptibility, and atherosclerosis in hypercholesterolemic hamsters." Journal of Agricultural and Food Chemistry 46.4 (1998): 1453-1459.